DNMT1

Summary

DNMT1 (DNA methyltransferase 1, HGNC:2976) is a protein-coding gene on chromosome 19p13.2, encoding DNA (cytosine-5)-methyltransferase 1 (P26358). DNA methyltransferase that methylates CpG residues. In precision oncology, DNMT1 EXPRESSION is associated with resistance to Cisplatin in Gastric Adenocarcinoma (CIViC Level B); 1 further curated variant–drug associations are listed below. It is a selective cancer dependency (DepMap: 70.8% of cell lines).

This gene encodes an enzyme that transfers methyl groups to cytosine nucleotides of genomic DNA. This protein is the major enzyme responsible for maintaining methylation patterns following DNA replication and shows a preference for hemi-methylated DNA. Methylation of DNA is an important component of mammalian epigenetic gene regulation. Aberrant methylation patterns are found in human tumors and associated with developmental abnormalities. Variation in this gene has been associated with cerebellar ataxia, deafness, and narcolepsy, and neuropathy, hereditary sensory, type IE. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1786 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant cerebellar ataxia, deafness and narcolepsy (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 1,684 total — 3 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 48
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Cancer dependency (DepMap): dependent in 70.8% of screened cell lines
• Transcription factor: yes — 199 downstream targets (CollecTRI)
• MANE Select transcript: NM_001130823

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2976
Approved symbol	DNMT1
Name	DNA methyltransferase 1
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	MCMT, CXXC9
Ensembl gene	ENSG00000130816
Ensembl biotype	protein_coding
OMIM	126375
Entrez	1786

Gene structure

Transcript identifiers

Ensembl transcripts: 56 — 24 retained_intron, 17 protein_coding, 9 nonsense_mediated_decay, 6 protein_coding_CDS_not_defined

ENST00000340748, ENST00000359526, ENST00000585843, ENST00000585920, ENST00000586086, ENST00000586588, ENST00000586667, ENST00000586799, ENST00000586800, ENST00000586988, ENST00000587197, ENST00000587604, ENST00000588118, ENST00000588913, ENST00000588952, ENST00000589091, ENST00000589294, ENST00000589349, ENST00000589351, ENST00000589538, ENST00000590619, ENST00000591239, ENST00000591764, ENST00000591798, ENST00000592054, ENST00000592342, ENST00000592705, ENST00000593049, ENST00000676604, ENST00000676610, ENST00000676820, ENST00000676868, ENST00000677013, ENST00000677038, ENST00000677135, ENST00000677250, ENST00000677616, ENST00000677634, ENST00000677685, ENST00000677783, ENST00000677946, ENST00000678024, ENST00000678107, ENST00000678239, ENST00000678647, ENST00000678694, ENST00000678804, ENST00000678851, ENST00000678957, ENST00000679100, ENST00000679103, ENST00000679313, ENST00000917926, ENST00000917927, ENST00000917928, ENST00000917929

RefSeq mRNA: 4 — MANE Select: NM_001130823 NM_001130823, NM_001318730, NM_001318731, NM_001379

CCDS: CCDS12228, CCDS45958

Canonical transcript exons

ENST00000359526 — 41 exons

Exon	Start	End
ENSE00001060736	10194820	10194953
ENSE00003459610	10168330	10168364
ENSE00003460142	10140046	10140328
ENSE00003468764	10137832	10138009
ENSE00003473973	10133346	10133701
ENSE00003480315	10151398	10151545
ENSE00003481219	10146351	10146524
ENSE00003497876	10151750	10151847
ENSE00003504718	10148884	10149017
ENSE00003527146	10160384	10160418
ENSE00003529251	10182041	10182077
ENSE00003534678	10142028	10142220
ENSE00003538226	10155853	10155945
ENSE00003538537	10135736	10135852
ENSE00003540759	10138439	10138605
ENSE00003551309	10140781	10140909
ENSE00003554024	10141105	10141189
ENSE00003572634	10166598	10166685
ENSE00003586638	10180187	10180234
ENSE00003591662	10180778	10180885
ENSE00003595657	10159658	10159767
ENSE00003601320	10154905	10155056
ENSE00003605221	10173871	10173905
ENSE00003606243	10156391	10156509
ENSE00003615043	10154586	10154773
ENSE00003624605	10180350	10180569
ENSE00003627171	10149853	10149968
ENSE00003632609	10137085	10137280
ENSE00003633700	10177292	10177367
ENSE00003636455	10154293	10154479
ENSE00003642371	10159842	10159922
ENSE00003666086	10139676	10139817
ENSE00003666942	10134217	10134307
ENSE00003675707	10136121	10136287
ENSE00003676029	10149453	10149657
ENSE00003678102	10143766	10143987
ENSE00003680616	10163326	10163360
ENSE00003690205	10162667	10162748
ENSE00003751346	10160018	10160063
ENSE00003784265	10173090	10173174
ENSE00003788993	10175540	10175618

Expression profiles

Bgee: expression breadth ubiquitous, 266 present calls, max score 99.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.1327 / max 661.5205, expressed in 1817 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179086	38.7128	1812
179094	1.1556	625
179083	0.9008	515
179087	0.8653	534
179078	0.8090	407
179085	0.3480	172
179077	0.3090	64
179090	0.0112	6
179089	0.0083	5
179088	0.0071	3

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	99.93	gold quality
secondary oocyte	CL:0000655	99.87	gold quality
sural nerve	UBERON:0015488	97.85	gold quality
ventricular zone	UBERON:0003053	96.53	gold quality
ganglionic eminence	UBERON:0004023	95.95	gold quality
embryo	UBERON:0000922	95.93	gold quality
bone marrow cell	CL:0002092	95.71	gold quality
vermiform appendix	UBERON:0001154	95.21	gold quality
cerebellar hemisphere	UBERON:0002245	95.04	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.03	gold quality
cerebellar cortex	UBERON:0002129	94.99	gold quality
lymph node	UBERON:0000029	94.94	gold quality
calcaneal tendon	UBERON:0003701	94.94	gold quality
cortical plate	UBERON:0005343	94.91	gold quality
right testis	UBERON:0004534	94.54	gold quality
placenta	UBERON:0001987	94.53	gold quality
cerebellum	UBERON:0002037	94.48	gold quality
left testis	UBERON:0004533	93.99	gold quality
caecum	UBERON:0001153	93.79	gold quality
granulocyte	CL:0000094	93.38	gold quality
thymus	UBERON:0002370	93.35	silver quality
trabecular bone tissue	UBERON:0002483	93.01	gold quality
testis	UBERON:0000473	92.70	gold quality
adult organism	UBERON:0007023	92.21	gold quality
mucosa of transverse colon	UBERON:0004991	92.16	gold quality
tonsil	UBERON:0002372	91.98	gold quality
epithelium of nasopharynx	UBERON:0001951	91.96	silver quality
upper lobe of left lung	UBERON:0008952	91.89	gold quality
upper lobe of lung	UBERON:0008948	91.75	gold quality
spleen	UBERON:0002106	91.68	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	9124.02
E-MTAB-6701	yes	124.28
E-CURD-112	yes	36.33
E-CURD-122	yes	25.56
E-HCAD-13	yes	20.51
E-HCAD-1	yes	17.29
E-MTAB-6678	yes	10.25
E-ANND-3	yes	8.22
E-CURD-53	no	704.04

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

199 targets.

Target	Regulation
ABCA1
ABCB1
ADAM2
ADH1C
AGO1
AHSG
ALB
ALDH3B1
ALOX15	Unknown
APC
AR
ASCL1
ATP11C
BAG1	Unknown
BAG3	Activation
BAG4	Activation
BBC3
BCL2
BCL2L11
BIRC5	Repression
BMP2	Repression
BRCA1
BRMS1
CADM1
CASP8	Repression
CAT
CBX1
CCNA2
CCNB2
CD2

Upstream regulators (CollecTRI, top): APC, CDKN1A, CTNNB1, DMAP1, DNMT1, DNMT3B, E2F1, EP300, ESR1, ESRRG, HBP1, HDAC1, HDAC2, IRF4, MTF1, NANOG, NFKB1, NFKB, NPM1, NR0B2, PARP1, POU5F1, RELA, SP1, SP3, STAT3, TBXT, TP53

miRNA regulators (miRDB)

33 targeting DNMT1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-5094	98.63	67.11	1062

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 70.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• recruited to the RARbeta2 promoter by the PML-RAR fusion protein (PMID:11834837)
• DNMT1 and DNMT3b cooperate to silence genes in human cancer cells (PMID:11932749)
• the human de novo enzymes hDNMT3a and hDNMT3b form complexes with the major maintenance enzyme hDNMT1. (PMID:12145218)
• DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. (PMID:12496760)
• DNMT1 gene copy number does not influence susceptibility to development of malignant lymphoproliferative disease. (PMID:12530095)
• Human DNA methyltransferase gene DNMT1 is regulated by the APC pathway (PMID:12538344)
• DNA methylation is tightly coupled to replication through physical interaction of DNMT1 and core components of the replication machinery. (PMID:12548018)
• reduction in DNMT1 triggers intra-S-phase arrest of DNA replication proposed to protect the genome from extensive DNA demethylation. (PMID:12576480)
• Decrease of DNA methyltransferase 1 expression relative to cell proliferation in transitional cell carcinoma. (PMID:12594811)
• mutational inactivation of the DNMT1 gene that potentially causes a genome-wide alteration of DNA methylation status may be a rare event during human carcinogenesis (PMID:12637155)
• Over-expressed in squamous cell carcinoma of the mouth. (PMID:12738984)
• We investigated occupancy of ER-alpha promoter by pRb2/p130-E2F4/5-HDAC1-SUV39 H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1 complexes, and provided a link between pRb2/p130 and chromatin-modifying enzymes in the regulation of ER-alpha transcription (PMID:12789259)
• structural homology model for human DNA methyltransferase 1 (PMID:12804601)
• DNMT1 plays a key role in methylation maintenance, DNMT3b may act as an accessory to support the function in ovarian cancer cells. (PMID:14559786)
• gene expression as a likely mechansism in underlying causes of changes in DNA methylation in aging and tumorigenesis (PMID:14577574)
• Activation of p53 reduces binding and relieves transcriptional repression of the Dnmt1gene, whereas loss of p53, a frequent, early event in tumorigenesis, may significantly contribute to aberrant genomic methylation. (PMID:14583449)
• hypothesis that the increase of DNA-methyltransferase 1 expression in telencephalic GABAergic interneurons of schizophrenia patients causes a promoter hypermethylation of reelin and GAD(67) and perhaps of other genes expressed in these interneurons (PMID:14684836)
• DNA methyltransferase 1 knock down induces gene expression by a mechanism independent of DNA methylation and histone deacetylation (PMID:15087453)
• DNMT1 activity contributes to the preservation of the correct organization of large heterochromatic regions (PMID:15220328)
• inhibition of DNA methylation by DNMT1 by an antisense oligodeoxynucleotide influences cell morphology and adhesion (PMID:15289832)
• Expression levels of DNMT1 in tumor cells may affect the effectiveness of doxorubicin in chemotherapy. (PMID:15340041)
• The average mRNA level of Dnmt1 gene from cancerous tissue was higher and that of mbd2 gene from cancerous tissue was lower than that from non-cancerous tissue (PMID:15526354)
• DNMT1- and p53-mediated methylation of the survivin promoter, suggesting cooperation between p53 and DNMT1 in gene silencing. (PMID:15657147)
• Results suggest a novel mechanism for gene silencing mediated by RUNX1/MTG8 and support the combination of HDAC and DNMT inhibitors as a novel therapeutic approach for t(8;21) AML. (PMID:15735013)
• DNMT1 protein levels are elevated in breast cancer tissues and in MCF-7 breast cancer cells relative to normal human mammary epithelial cells without a concomitant increase in DNMT1 mRNA or proliferative fraction. (PMID:15755728)
• Increased DNMT1 gene expression appears to be in lymphomas and maybe associated with oncogenesis in this group of tumors. (PMID:15762053)
• Unlike Dnmt1, pre-existing cytosine methylation at CpG sites or non-CpG sites does not stimulate Dnmt3a activity in vitro and in vivo. (PMID:15799776)
• STAT3 may transform cells by inducing epigenetic silencing of SHP-1 in cooperation with DNMT1 and histone deacetylase 1 (PMID:15870198)
• Direct role of Dnmt1 in the restoration of epigenetic information during DNA repair. (PMID:15956212)
• These data suggest that increased DNMT1 protein expression participates in multistage pancreatic carcinogenesis from the precancerous stage to malignant progression of ductal carcinomas and may be a biological predictor of poor prognosis. (PMID:16053511)
• necessary for both class switching and somatic hypermutation in B cells (PMID:16227093)
• DNMT1 is necessary for proper PcG body assembly independent of DNMT-associated histone deacetylase activity. (PMID:16314526)
• Breast cancer cells have a prominent loss of DNA methylation accompanied by altered expression of maintenance DNA methyltransferase DNMT1. (PMID:16322686)
• data suggests a potential role for DNMT1 in the initiation of promoter CpG island hypermethylation in human cancer cells (PMID:16423997)
• human cancer cells may differ in their reliance on DNMT1 for maintaining DNA methylation (PMID:16424002)
• down-regulation of DNMT1 methyltransferase leads to activation and stable hypomethylation of MAGE-A1 in melanoma cells (PMID:16497664)
• DNMT1 protein overexpression may be responsible for aberrant DNA methylation during multistage carcinogenesis of the pancreas (PMID:16537562)
• In human cells maintenance of XIST methylation is controlled differently than global genomic methylation and in the absence of both DNMT1 and DNMT3B. (PMID:16769694)
• Inhibitors of DNMT1 may have clinical relevance for immune modulation by augmentation of cytokine effects and/or expression of tumor-associated antigens. (PMID:16801630)
• STAT3 binds in vitro to 2 STAT3 SIE/GAS-binding sites identified in promoter 1 and enhancer 1 of the DNMT1 gene (PMID:16861352)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dnmt1	ENSDARG00000030756
mus_musculus	Dnmt1	ENSMUSG00000004099
rattus_norvegicus	Dnmt1	ENSRNOG00000039859

Paralogs (1): TRDMT1 (ENSG00000107614)

Protein

Protein identifiers

DNA (cytosine-5)-methyltransferase 1 — P26358 (reviewed: P26358)

Alternative names: CXXC-type zinc finger protein 9, DNA methyltransferase HsaI, MCMT

All UniProt accessions (20): P26358, A0A7I2V2G5, A0A7I2V311, A0A7I2V3F8, A0A7I2V490, A0A7I2V5D0, A0A7I2V5F1, A0A7I2V5F6, A0A7I2YQA8, A0A7I2YQQ0, K7EIZ6, K7EJL0, K7EKC3, K7ELB1, K7EMU8, K7ENQ6, K7ENW7, K7EP77, K7ER10, K7ERQ1

UniProt curated annotations — full annotation on UniProt →

Function. DNA methyltransferase that methylates CpG residues. Preferentially methylates hemimethylated DNA. Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is essential for epigenetic inheritance. Associates with chromatin during G2 and M phases to maintain DNA methylation independently of replication. It is responsible for maintaining methylation patterns established in development. DNA methylation is coordinated with methylation of histones. Mediates transcriptional repression by direct binding to HDAC2. In association with DNMT3B and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9. Probably forms a corepressor complex required for activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) or other tumor-related genes in colorectal cancer (CRC) cells. Also required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs). Associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing.

Subunit / interactions. Homodimer. Forms a stable complex with E2F1, BB1 and HDAC1. Forms a complex with DMAP1 and HDAC2, with direct interaction. Interacts with the PRC2/EED-EZH2 complex. Probably part of a corepressor complex containing ZNF304, TRIM28, SETDB1 and DNMT1. Interacts with UHRF1; promoting its recruitment to hemimethylated DNA. Interacts with USP7, promoting its deubiquitination. Interacts with PCNA. Interacts with MBD2 and MBD3. Interacts with DNMT3A and DNMT3B. Interacts with UBC9. Interacts with CSNK1D. Interacts with HDAC1. Interacts with BAZ2A/TIP5. Interacts with SIRT7. Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression. Interacts with L3MBTL3 and DCAF5; the interaction requires DNMT1 methylation at Lys-142 and is necessary to target DNMT1 for ubiquitination by the CRL4-DCAF5 E3 ubiquitin ligase complex and proteasomal degradation. Interacts with PHF20L1; the interaction requires DNMT1 methylation at Lys-142 and protects DNMT1 from ubiquitination and proteasomal degradation.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Ubiquitous; highly expressed in fetal tissues, heart, kidney, placenta, peripheral blood mononuclear cells, and expressed at lower levels in spleen, lung, brain, small intestine, colon, liver, and skeletal muscle. Isoform 2 is less expressed than isoform 1.

Post-translational modifications. Sumoylated; sumoylation increases activity. Acetylation on multiple lysines, mainly by KAT2B/PCAF, regulates cell cycle G(2)/M transition. Deacetylation of Lys-1349 and Lys-1415 by SIRT1 increases methyltransferase activity. Phosphorylation of Ser-154 by CDKs is important for enzymatic activity and protein stability. Phosphorylation of Ser-143 by AKT1 prevents methylation by SETD7 thereby increasing DNMT1 stability. Methylation at Lys-142 by SETD7 is necessary for the regulation of DNMT1 proteasomal degradation. Ubiquitinated by UHRF1; interaction with USP7 counteracts ubiquitination by UHRF1 by promoting deubiquitination and preventing degradation by the proteasome.

Disease relevance. Neuropathy, hereditary sensory, 1E (HSN1E) [MIM:614116] A neurodegenerative disorder characterized by adult onset of progressive peripheral sensory loss associated with progressive hearing impairment and early-onset dementia. The disease is caused by variants affecting the gene represented in this entry. Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant (ADCADN) [MIM:604121] An autosomal dominant neurologic disorder characterized by adult onset of progressive cerebellar ataxia, narcolepsy, cataplexy, sensorineural deafness, and dementia. More variable features include optic atrophy, sensory neuropathy, psychosis, and depression. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The RFTS domain specifically recognizes and binds histone H3 monoubiquitinated at two sites, either at ‘Lys-14’, ‘Lys-18’ and/or ‘Lys-23’ (H3K14ub, H3K18ub and H3K23ub, respectively). These histone marks are present at hemimethylated DNA sites at replication forks and act as docking site for DNMT1. In absence of H3K14ub, H3K18ub and H3K23ub chromatin marks, the RFTS domain inhibits the DNA methyltransferase activity by forming hydrogen bonds with the catalytic center. Binding to ubiquitinated histones relieves inhibition. The CXXC-type zinc finger specifically binds to unmethylated CpG dinucleotides, positioning the autoinhibitory linker between the DNA and the active site, thus providing a mechanism to ensure that only hemimethylated CpG dinucleotides undergo methylation.

Induction. Its abundance is reduced to non detectable levels at the G0 phase of the cell cycle and is dramatically induced upon entrance into the S-phase of the cell cycle.

Similarity. Belongs to the class I-like SAM-binding methyltransferase superfamily. C5-methyltransferase family.

Isoforms (3)

UniProt ID	Names	Canonical?
P26358-1	1	yes
P26358-2	2, Dnmt1b
P26358-3	3

RefSeq proteins (4): NP_001124295, NP_001305659, NP_001305660, NP_001370 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001025	BAH_dom	Domain
IPR001525	C5_MeTfrase	Family
IPR002857	Znf_CXXC	Domain
IPR010506	DMAP1-bd	Domain
IPR018117	C5_DNA_meth_AS	Active_site
IPR022702	DNMT1-RFD	Domain
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily
IPR031303	C5_meth_CS	Conserved_site
IPR043151	BAH_sf	Homologous_superfamily
IPR050390	C5-Methyltransferase	Family

Pfam: PF00145, PF01426, PF02008, PF06464, PF12047

Enzyme classification (BRENDA):

• EC 2.1.1.37 — DNA (cytosine-5-)-methyltransferase (BRENDA: 52 organisms, 225 substrates, 140 inhibitors, 78 Km, 31 kcat entries)

Substrate kinetics (BRENDA)

31 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
S-ADENOSYL-L-METHIONINE	0.0001–0.021	28
DNA	0.0003–0.092	4
POLY(DG-DC)-POLY(DG-DC)	0.0009–0.0035	4
POLY(DI-DC)-POLY(DI-DC)	0.0003–0.0015	3
POLY-(DI-DC)/POLY(DI-DC)	0.0005–0.0008	3
DGDC	0.0005–0.0016	2
DIDC	0.0004–0.0012	2
MONONUCLEOSOMAL DNA CONTAINING CYTOSINE	0.52–1.4	2
POLY(DI-DC)*POLY(DI-DC)	0.0005–0.0007	2
UNMETHYLATED 30-MER DNA CONTAINING CYTOSINE	—	2
(CGG*CCG)12	0.0008	1
(CGG*CCG)73	0.0001	1
CPNPG	0.0001	1
CPNPN	—	1
HEMIMETHYLATED CPG	—	1

Catalyzed reactions (Rhea), 1 shown:

• a 2’-deoxycytidine in DNA + S-adenosyl-L-methionine = a 5-methyl-2’-deoxycytidine in DNA + S-adenosyl-L-homocysteine + H(+) (RHEA:13681)

UniProt features (260 total): strand 60, helix 55, modified residue 37, binding site 28, mutagenesis site 18, region of interest 15, turn 14, sequence variant 7, compositionally biased region 7, repeat 6, domain 5, cross-link 2, splice variant 2, chain 1, zinc finger region 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

27 structures.

PDB	Method	Resolution (Å)
6X9J	X-RAY DIFFRACTION	1.79
6L1F	X-RAY DIFFRACTION	1.9
7SFC	X-RAY DIFFRACTION	1.97
5WVO	X-RAY DIFFRACTION	2
5YDR	X-RAY DIFFRACTION	2
7SFF	X-RAY DIFFRACTION	2.05
7SFD	X-RAY DIFFRACTION	2.09
6X9I	X-RAY DIFFRACTION	2.2
7XIB	ELECTRON MICROSCOPY	2.23
6K3A	X-RAY DIFFRACTION	2.3
3EPZ	X-RAY DIFFRACTION	2.31
7SFG	X-RAY DIFFRACTION	2.43
3SWR	X-RAY DIFFRACTION	2.49
7XI9	ELECTRON MICROSCOPY	2.52
7SFE	X-RAY DIFFRACTION	2.55
4WXX	X-RAY DIFFRACTION	2.62
6X9K	X-RAY DIFFRACTION	2.65
9V36	ELECTRON MICROSCOPY	2.77
4Z96	X-RAY DIFFRACTION	2.85
9V5P	ELECTRON MICROSCOPY	2.85
4YOC	X-RAY DIFFRACTION	2.92
4Z97	X-RAY DIFFRACTION	3
8XQC	ELECTRON MICROSCOPY	3.25
9K2W	ELECTRON MICROSCOPY	3.54
3PTA	X-RAY DIFFRACTION	3.6
9K2X	ELECTRON MICROSCOPY	3.75
8V9U	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P26358-F1	77.88	0.47

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 1226

Ligand- & substrate-binding residues (28): 353; 356; 414; 418; 653; 656; 659; 664; 667; 670; 686; 691 …

Post-translational modifications (39): 1349, 1415, 259, 1609, 70, 127, 133, 137, 141, 142, 143, 152, 154, 160, 166, 173, 188, 259, 312, 366 …

Mutagenesis-validated functional residues (18):

Position	Phenotype
142	loss of interaction with l3mbtl3 and dcaf5. loss of ubiquitination by the crl4-dcaf5 e3 ubiquitin ligase complex.
163	abolishes interaction with pcna.
164	abolishes interaction with pcna.
166	abolishes interaction with pcna.
167	abolishes interaction with pcna.
169	no loss of interaction with pcna.
170	abolishes interaction with pcna.
171	abolishes interaction with pcna.
172	no loss of interaction with pcna.
173	no loss of interaction with pcna.
582	slightly increased association with hemimethylated dna.
653	reduces activity about 10-fold; when associated with g-656; g-659; g-664; g-667 and g-670.
656	reduces activity about 10-fold; when associated with g-653; g-659; g-664; g-667 and g-670.
659	reduces activity about 10-fold; when associated with g-653; g-656; g-664; g-667 and g-670.
664	reduces activity about 10-fold; when associated with g-653; g-656; g-659; g-667 and g-670.
667	reduces activity about 10-fold; when associated with g-653; g-656; g-659; g-664 and g-670.
670	reduces activity about 10-fold; when associated with g-653; g-656; g-659; g-664 and g-667.
1226	loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-212300	PRC2 methylates histones and DNA
R-HSA-427413	NoRC negatively regulates rRNA expression
R-HSA-4655427	SUMOylation of DNA methylation proteins
R-HSA-5334118	DNA methylation
R-HSA-9701898	STAT3 nuclear events downstream of ALK signaling
R-HSA-9710421	Defective pyroptosis
R-HSA-9725371	Nuclear events stimulated by ALK signaling in cancer

MSigDB gene sets: 491 (showing top): E2F_Q4, MORF_DNMT1, E2F_Q4_01, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, MORF_ESPL1, TGCGCANK_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, E2F4DP1_01, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, KEGG_CYSTEINE_AND_METHIONINE_METABOLISM, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, MORF_RRM1

GO Biological Process (18): negative regulation of transcription by RNA polymerase II (GO:0000122), DNA methylation-dependent constitutive heterochromatin formation (GO:0006346), DNA-templated transcription (GO:0006351), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), methylation (GO:0032259), epigenetic programming of gene expression (GO:0043045), negative regulation of gene expression via chromosomal CpG island methylation (GO:0044027), cellular response to amino acid stimulus (GO:0071230), chromosomal DNA methylation maintenance following DNA replication (GO:0141119), cellular response to bisphenol A (GO:1903926), positive regulation of vascular associated smooth muscle cell proliferation (GO:1904707), negative regulation of vascular associated smooth muscle cell apoptotic process (GO:1905460), obsolete negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching (GO:1905931), chromatin organization (GO:0006325), regulation of gene expression (GO:0010468), regulation of cell population proliferation (GO:0042127), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (16): DNA binding (GO:0003677), DNA (cytosine-5-)-methyltransferase activity (GO:0003886), zinc ion binding (GO:0008270), methyl-CpG binding (GO:0008327), DNA-methyltransferase activity (GO:0009008), lncRNA binding (GO:0106222), histone H3K18ub reader activity (GO:0140254), histone H3K23ub reader activity (GO:0140257), histone H3K14ub reader activity (GO:0140258), promoter-specific chromatin binding (GO:1990841), chromatin binding (GO:0003682), RNA binding (GO:0003723), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (8): heterochromatin (GO:0000792), female germ cell nucleus (GO:0001674), nucleus (GO:0005634), nucleoplasm (GO:0005654), replication fork (GO:0005657), pericentric heterochromatin (GO:0005721), mitochondrion (GO:0005739), germ cell nucleus (GO:0043073)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Epigenetic regulation of gene expression	2
Negative epigenetic regulation of rRNA expression	1
SUMO E3 ligases SUMOylate target proteins	1
Signaling by ALK	1
Diseases of programmed cell death	1
Signaling by ALK fusions and activated point mutants	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
gene expression	4
histone H3 reader activity	3
regulation of gene expression	2
nucleic acid binding	2
binding	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
constitutive heterochromatin formation	1
RNA biosynthetic process	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
metabolic process	1
epigenetic regulation of gene expression	1
negative regulation of gene expression, epigenetic	1
response to amino acid	1
cellular response to acid chemical	1
chromatin organization	1
cellular response to oxygen-containing compound	1
response to bisphenol A	1
positive regulation of smooth muscle cell proliferation	1
regulation of vascular associated smooth muscle cell proliferation	1
vascular associated smooth muscle cell proliferation	1
negative regulation of smooth muscle cell apoptotic process	1
vascular associated smooth muscle cell apoptotic process	1
regulation of vascular associated smooth muscle cell apoptotic process	1
cellular component organization	1
regulation of macromolecule biosynthetic process	1
cell population proliferation	1
regulation of cellular process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
S-adenosylmethionine-dependent methyltransferase activity	1
DNA-methyltransferase activity	1
transition metal ion binding	1
nucleotide binding	1
sequence-specific DNA binding	1

Protein interactions and networks

STRING

6465 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNMT1	DNMT3B	Q9UBC3	999
DNMT1	UHRF1	Q96T88	999
DNMT1	EZH2	Q15910	998
DNMT1	HDAC1	Q13547	998
DNMT1	SUV39H1	O43463	997
DNMT1	MECP2	P51608	997
DNMT1	HDAC2	Q92769	997
DNMT1	KDM1A	O60341	996
DNMT1	DMAP1	Q9NPF5	996
DNMT1	DNMT3A	Q9Y6K1	995
DNMT1	EHMT2	Q96KQ7	995
DNMT1	TP53	P04637	994
DNMT1	SNAI1	O95863	991
DNMT1	H3-3A	P06351	973
DNMT1	H3C14	Q71DI3	973
DNMT1	H3-5	Q6NXT2	973

IntAct

196 interactions, top by confidence:

A	B	Type	Score
EZH2	EED	psi-mi:“MI:0914”(association)	0.930
SIRT1	DNMT1	psi-mi:“MI:0407”(direct interaction)	0.750
SIRT1	DNMT1	psi-mi:“MI:0403”(colocalization)	0.750
SIRT1	DNMT1	psi-mi:“MI:0915”(physical association)	0.750
DNMT1	SIRT1	psi-mi:“MI:0915”(physical association)	0.750
SETD7	DNMT1	psi-mi:“MI:0213”(methylation reaction)	0.740
SETD7	DNMT1	psi-mi:“MI:0407”(direct interaction)	0.740
DNMT1	SETD7	psi-mi:“MI:0915”(physical association)	0.740
DNMT1	SETD7	psi-mi:“MI:0407”(direct interaction)	0.740
DNMT1	SETD7	psi-mi:“MI:0213”(methylation reaction)	0.740
UHRF1	DNMT1	psi-mi:“MI:0915”(physical association)	0.700
UHRF1	DNMT1	psi-mi:“MI:0914”(association)	0.700
UHRF1	DNMT1	psi-mi:“MI:0403”(colocalization)	0.700
DNMT1	UHRF1	psi-mi:“MI:0403”(colocalization)	0.700
	DNMT1	psi-mi:“MI:0915”(physical association)	0.700
DNMT1		psi-mi:“MI:0915”(physical association)	0.700
DNMT1	EZH2	psi-mi:“MI:0914”(association)	0.690

BioGRID (518): DNMT1 (Affinity Capture-MS), DNMT1 (Affinity Capture-MS), DNMT1 (Co-fractionation), DNMT1 (Co-fractionation), DNMT1 (Co-fractionation), MTA1 (Co-fractionation), DNMT1 (Affinity Capture-MS), UHRF1 (Affinity Capture-Western), HIST3H3 (Affinity Capture-Western), HIST2H2AC (Affinity Capture-Western), DNMT1 (Proximity Label-MS), DNMT1 (Affinity Capture-MS), DNMT1 (Affinity Capture-MS), DNMT1 (Affinity Capture-MS), DNMT1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0K3AXH1, A1A708, A1CZE5, A2R9H9, E9P860, F4I2J8, G5EDM7, G5EFV3, G5EG14, G5EGK6, K8ERR8, O44548, O44757, P13864, P20193, P26358, P34427, P34437, P34544, P38827, P46012, Q05471, Q09268, Q09842, Q11107, Q21341, Q22811, Q22992, Q24K09, Q2GWF3, Q2UTQ9, Q4WTV7, Q60JJ0, Q6BER5, Q6CIT4, Q6CNY4, Q6FKB1, Q74Z27, Q75D88, Q7PK92

Diamond homologs: A0A0P0VUY4, B1Q3J6, C0SQ89, D4ZX35, G3V8T1, J9VQZ0, O23273, O33481, O49139, P13864, P16668, P23737, P25265, P26358, P31033, P34881, P50196, Q24K09, Q27746, Q3TYA6, Q57983, Q5KQL9, Q7Y1I7, Q8LPU5, Q8N8U2, Q92072, Q94F87, Q94F88, Q99549, Q9ARI6, Q9AXT8, Q9M0S8, Q9T0I1, Q9WTK2, P08455, P34877, P34883, P34905, P50185, P94147

SIGNOR signaling

26 interactions.

A	Effect	B	Mechanism
AKT1	up-regulates	DNMT1	phosphorylation
CDK1	up-regulates	DNMT1	phosphorylation
CDK2	up-regulates	DNMT1	phosphorylation
CDK5	up-regulates	DNMT1	phosphorylation
AKT	up-regulates	DNMT1	phosphorylation
NANOG	“up-regulates quantity by expression”	DNMT1	“transcriptional regulation”
POU5F1	“up-regulates quantity by expression”	DNMT1	“transcriptional regulation”
DNMT1	“down-regulates quantity by repression”	ESR1	“transcriptional regulation”
HDAC1	“down-regulates quantity by repression”	DNMT1	“transcriptional regulation”
DNMT1	“up-regulates quantity by expression”	BAG1	“transcriptional regulation”
DNMT1	“up-regulates quantity by expression”	BAG3	“transcriptional regulation”
DNMT1	“up-regulates quantity by expression”	BAG4	“transcriptional regulation”
DNMT1	“down-regulates quantity by repression”	IL32	“transcriptional regulation”
DNMT1	“down-regulates quantity by repression”	MBD2	“transcriptional regulation”
DNMT1	“down-regulates quantity by repression”	GAD1	“transcriptional regulation”
DNMT1	“down-regulates quantity by repression”	RELN	“transcriptional regulation”
5-azacytidine	“down-regulates activity”	DNMT1	“chemical inhibition”
5-aza-2’-deoxycytidine	“down-regulates activity”	DNMT1	“chemical inhibition”
MECP2	“up-regulates activity”	DNMT1	binding
DNMT1	“down-regulates quantity by repression”	FOXP3	“transcriptional regulation”
GSK3B	“down-regulates quantity”	DNMT1	phosphorylation
DNMT1	“form complex”	DNMT1/DNMT3A	binding
DNMT1	“form complex”	DNMT1/DNMT3B	binding
PRKAA1	“down-regulates activity”	DNMT1	phosphorylation
RBBP7	“down-regulates activity”	DNMT1	binding
AMPK	“down-regulates activity”	DNMT1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 110 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	5	43.3×	9e-06
Activation of BH3-only proteins	5	28.2×	5e-05
FOXO-mediated transcription	5	19.1×	2e-04
RHO GTPases activate PKNs	5	18.0×	2e-04
Intrinsic Pathway for Apoptosis	5	16.6×	3e-04
Regulation of PTEN gene transcription	8	16.2×	5e-06
Transcriptional and post-translational regulation of MITF-M expression and activity	8	16.2×	5e-06
SARS-CoV-1-host interactions	7	14.0×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of gene expression, epigenetic	5	20.7×	6e-04
cellular response to UV	6	18.3×	2e-04
cellular response to glucose starvation	5	17.4×	1e-03
heterochromatin formation	6	15.8×	4e-04
rhythmic process	6	15.6×	4e-04
regulation of circadian rhythm	5	13.4×	3e-03
chromatin organization	9	9.2×	2e-04
chromatin remodeling	10	7.5×	2e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

1684 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	7
Uncertain significance	653
Likely benign	734
Benign	101

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
162188	NM_001130823.3(DNMT1):c.1531T>C (p.Tyr511His)	Pathogenic
29683	NM_001130823.3(DNMT1):c.1518_1520delinsATA (p.Asp506_Pro507delinsGluTyr)	Pathogenic
50920	NM_001130823.3(DNMT1):c.1709C>T (p.Ala570Val)	Pathogenic
1027527	NM_001130823.3(DNMT1):c.4636C>T (p.Pro1546Ser)	Likely pathogenic
1067356	NM_001130823.3(DNMT1):c.1619A>C (p.Tyr540Ser)	Likely pathogenic
3777752	NM_001130823.3(DNMT1):c.2327G>A (p.Gly776Glu)	Likely pathogenic
50919	NM_001130823.3(DNMT1):c.1816G>T (p.Val606Phe)	Likely pathogenic
50921	NM_001130823.3(DNMT1):c.1814G>C (p.Gly605Ala)	Likely pathogenic
976693	NM_001130823.3(DNMT1):c.1823T>G (p.Leu608Arg)	Likely pathogenic
978575	NM_001130823.3(DNMT1):c.2858A>G (p.Asp953Gly)	Likely pathogenic

SpliceAI

5978 predictions. Top by Δscore:

Variant	Effect	Δscore
19:10134303:CCCAC:C	acceptor_gain	1.0000
19:10134304:CCAC:C	acceptor_gain	1.0000
19:10134304:CCACC:C	acceptor_gain	1.0000
19:10134305:CACC:C	acceptor_gain	1.0000
19:10134306:ACC:A	acceptor_loss	1.0000
19:10134308:C:CA	acceptor_loss	1.0000
19:10134309:T:G	acceptor_loss	1.0000
19:10135731:CTGA:C	donor_loss	1.0000
19:10135733:GA:G	donor_loss	1.0000
19:10135734:A:C	donor_loss	1.0000
19:10135735:C:CA	donor_loss	1.0000
19:10135738:G:A	donor_gain	1.0000
19:10135848:CGGCC:C	acceptor_gain	1.0000
19:10135851:CC:C	acceptor_gain	1.0000
19:10135852:CC:C	acceptor_gain	1.0000
19:10135853:C:CC	acceptor_gain	1.0000
19:10135853:C:CG	acceptor_loss	1.0000
19:10135854:T:A	acceptor_loss	1.0000
19:10136118:TAC:T	donor_loss	1.0000
19:10136120:CCTG:C	donor_gain	1.0000
19:10136283:GCCGG:G	acceptor_gain	1.0000
19:10136284:CCGG:C	acceptor_gain	1.0000
19:10136284:CCGGC:C	acceptor_gain	1.0000
19:10136285:CGG:C	acceptor_gain	1.0000
19:10136285:CGGC:C	acceptor_gain	1.0000
19:10136286:GGCTG:G	acceptor_loss	1.0000
19:10136287:GCTGG:G	acceptor_loss	1.0000
19:10136288:C:CC	acceptor_gain	1.0000
19:10136288:CTG:C	acceptor_loss	1.0000
19:10137075:CAGGA:C	donor_gain	1.0000

AlphaMissense

10791 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:10134297:G:T	A1579D	1.000
19:10134298:C:G	A1579P	1.000
19:10134299:A:C	N1578K	1.000
19:10134299:A:T	N1578K	1.000
19:10134301:T:C	N1578D	1.000
19:10134303:C:A	G1577V	1.000
19:10134303:C:T	G1577D	1.000
19:10134304:C:A	G1577C	1.000
19:10134304:C:G	G1577R	1.000
19:10135740:C:G	R1574P	1.000
19:10135785:A:G	F1559S	1.000
19:10135789:C:G	G1558R	1.000
19:10135790:C:A	Q1557H	1.000
19:10135790:C:G	Q1557H	1.000
19:10135800:G:T	A1554D	1.000
19:10135814:G:C	S1549R	1.000
19:10135814:G:T	S1549R	1.000
19:10135816:T:G	S1549R	1.000
19:10135842:A:G	L1540P	1.000
19:10135842:A:T	L1540H	1.000
19:10135849:G:T	R1538S	1.000
19:10135851:C:A	G1537V	1.000
19:10135851:C:T	G1537D	1.000
19:10135852:C:A	G1537C	1.000
19:10135852:C:G	G1537R	1.000
19:10136121:C:A	Q1536H	1.000
19:10136121:C:G	Q1536H	1.000
19:10136124:C:A	K1535N	1.000
19:10136124:C:G	K1535N	1.000
19:10136126:T:C	K1535E	1.000

dbSNP variants (sampled 300 via entrez): RS1000003841 (19:10133059 C>A,T), RS1000008042 (19:10182961 T>C), RS1000013328 (19:10172023 A>G,T), RS1000031272 (19:10182858 G>A,C), RS1000142353 (19:10177951 A>G), RS1000196498 (19:10166326 T>C), RS1000202480 (19:10174858 C>A), RS1000420427 (19:10136082 G>A), RS1000446318 (19:10183070 CAT>C), RS1000467616 (19:10179126 CAAAAAAAAAAAAA>C,CA,CAA,CAAAAA,CAAAAAA,CAAAAAAA,CAAAAAAAA,CAAAAAAAAA,CAAAAAAAAAA,CAAAAAAAAAAA,CAAAAAAAAAAAA,CAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAAA), RS1000470674 (19:10161033 G>A), RS1000514532 (19:10136844 C>T), RS1000525548 (19:10167890 G>A), RS1000553873 (19:10134408 G>A,T), RS1000589382 (19:10185424 C>A)

Disease associations

OMIM: gene MIM:126375 | disease phenotypes: MIM:604121, MIM:614116, MIM:108600, MIM:130650, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant cerebellar ataxia, deafness and narcolepsy	Definitive	Unknown
hereditary sensory neuropathy-deafness-dementia syndrome	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autosomal dominant cerebellar ataxia, deafness and narcolepsy	Definitive	AD

Mondo (9): autosomal dominant cerebellar ataxia, deafness and narcolepsy (MONDO:0011397), hereditary sensory neuropathy-deafness-dementia syndrome (MONDO:0013584), spastic ataxia (MONDO:0017845), Beckwith-Wiedemann syndrome (MONDO:0007534), Charcot-Marie-Tooth disease (MONDO:0015626), cerebellar ataxia (MONDO:0000437), choreatic disease (MONDO:0001595), limb-girdle muscular dystrophy (MONDO:0016971), pituitary stalk interruption syndrome (MONDO:0019828)

Orphanet (10): Autosomal dominant cerebellar ataxia-deafness-narcolepsy syndrome (Orphanet:314404), Hereditary sensory neuropathy-deafness-dementia syndrome (Orphanet:456318), Spastic ataxia (Orphanet:316226), Beckwith-Wiedemann syndrome (Orphanet:116), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Rare ataxia (Orphanet:102002), Benign hereditary chorea (Orphanet:1429), Constitutional hemolytic anemia due to acanthocytosis (Orphanet:98366), Limb-girdle muscular dystrophy (Orphanet:263), Pituitary stalk interruption syndrome (Orphanet:95496)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000020	Urinary incontinence
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000518	Cataract
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000709	Psychosis
HP:0000716	Depression
HP:0000726	Dementia
HP:0000737	Irritability
HP:0000741	Apathy
HP:0000763	Sensory neuropathy
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001262	Excessive daytime somnolence
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001347	Hyperreflexia
HP:0002059	Cerebral atrophy
HP:0002200	Pseudobulbar signs
HP:0002322	Resting tremor
HP:0002346	Head tremor
HP:0002354	Memory impairment
HP:0002460	Distal muscle weakness
HP:0002476	Primitive reflex
HP:0002494	Abnormal rapid eye movement sleep
HP:0002500	Abnormal cerebral white matter morphology
HP:0002519	Hypnagogic hallucination

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002260_3	Narcolepsy	4.000000e-10
GCST004619_134	Reticulocyte fraction of red cells	3.000000e-23
GCST004622_71	Reticulocyte count	7.000000e-26
GCST004628_109	Immature fraction of reticulocytes	1.000000e-15
GCST008362_67	Birth weight	7.000000e-09
GCST008363_130	Offspring birth weight	5.000000e-07
GCST90000025_554	Appendicular lean mass	9.000000e-12
GCST90020025_1416	Waist-to-hip ratio adjusted for BMI	1.000000e-08
GCST90020027_127	Waist-hip index	9.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004980	appendicular lean mass
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D001506	Beckwith-Wiedemann Syndrome	C16.131.077.133; C16.131.260.080; C16.320.180.080; C16.320.447.375
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D002819	Chorea	C10.228.662.262.249; C10.597.350.250; C23.888.592.350.250
D049288	Muscular Dystrophies, Limb-Girdle	C05.651.534.500.280; C10.668.491.175.500.149; C16.320.577.280
C580162	Hereditary Sensory and Autonomic Neuropathy Type Ie (supp.)
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1993 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 248,787 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1201129	DECITABINE	4	58,183
CHEMBL1489	AZACITIDINE	4	97,123
CHEMBL617	CEPHALOTHIN	4	24,927
CHEMBL297453	EPIGALOCATECHIN GALLATE	3	22,804
CHEMBL1232461	MOLIBRESIB	2	1,538
CHEMBL44	GENISTEIN	2	44,212

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
DNMT1 EXPRESSION	Cisplatin	Gastric Adenocarcinoma	Resistance	CIViC B	EID946
DNMT1 EXPRESSION	Decitabine	Ovarian Cancer	Sensitivity/Response	CIViC D	EID819

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 2.1.1.- Methyltransferases

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
GSK3685032	Inhibition	6.64	pIC50
CM-272	Inhibition	6.44	pIC50
SGI-1027	Inhibition	6.07	pIC50
bromo-deaza-SAH	Inhibition	6.02	pKi

Binding affinities (BindingDB)

162 measured of 186 human assays (226 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
US10407423, Compound 1-02	IC50	300 nM	US-10407423: Compounds as inhibitors of DNA methyltransferases
US10407423, Compound 2-06	IC50	300 nM	US-10407423: Compounds as inhibitors of DNA methyltransferases
MLS000562014	IC50	408 nM
2-[[3,5-dicyano-4-ethyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-pyridinyl]sulfanyl]-2-phenylacetamide	IC50	660 nM	US-10975056: Substituted pyridines as inhibitors of DNMT1
US10407423, Compound 1-03	IC50	750 nM	US-10407423: Compounds as inhibitors of DNA methyltransferases
US10407423, Compound 1-05	IC50	750 nM	US-10407423: Compounds as inhibitors of DNA methyltransferases
US10407423, Compound 2-02	IC50	750 nM	US-10407423: Compounds as inhibitors of DNA methyltransferases
US10407423, Compound 2-04	IC50	750 nM	US-10407423: Compounds as inhibitors of DNA methyltransferases
US10407423, Compound 2-05	IC50	750 nM	US-10407423: Compounds as inhibitors of DNA methyltransferases
US10407423, Compound 2-07	IC50	750 nM	US-10407423: Compounds as inhibitors of DNA methyltransferases
US10407423, Compound 2-08	IC50	750 nM	US-10407423: Compounds as inhibitors of DNA methyltransferases
US10407423, Compound 2-09	IC50	750 nM	US-10407423: Compounds as inhibitors of DNA methyltransferases
US10407423, Compound 2-10	IC50	750 nM	US-10407423: Compounds as inhibitors of DNA methyltransferases
US10407423, Compound 2-12	IC50	750 nM	US-10407423: Compounds as inhibitors of DNA methyltransferases
US10407423, Compound 3-02	IC50	750 nM	US-10407423: Compounds as inhibitors of DNA methyltransferases
(E)-N-[2-[(N’‘E)-N’’-[1-(4-ethylphenyl)ethylidene]hydrazino]-2-keto-ethyl]-3-(2-furyl)acrylamide	IC50	844 nM
cid_2931173	IC50	1020 nM
cid_1728957	IC50	1020 nM
2-[3-[2-hydroxyethyl(dimethyl)azaniumyl]propanoylamino]-2-methyl-propane-1-sulfonate	EC50	1160 nM
2-[5-[(Z)-(3-bromanyl-8-oxidanylidene-[1,3]thiazolo[4,5]imidazo[1,2-b]pyridin-7-ylidene)methyl]furan-2-yl]benzoic acid	IC50	1250 nM
chrysene-5,6-dione	IC50	1340 nM
1-(3,4-Dichloro-phenyl)-3-(5-pyridin-4-yl-[1,3,4]thiadiazol-2-yl)-urea	IC50	1560 nM
cid_4790991	IC50	1620 nM
(4E)-2-(1,3-benzothiazol-2-yl)-5-[(4-chlorophenyl)sulfanylmethyl]-4-[(4-methoxyphenyl)methylidene]pyrazol-3-one	IC50	1690 nM
(6Z)-5-azanylidene-6-[[1-(3-chloranyl-4-methyl-phenyl)pyrrol-2-yl]methylidene]-3-methylsulfonyl-[1,2,4]thiadiazolo[4,5-a]pyrimidin-7-one	IC50	1860 nM
4-Ethyleniminonaphthoquinone-1,2	IC50	1870 nM
3-[2-({3-[2-(2,4-dimethylanilino)-2-oxoethyl]-2,4-dioxo-1,3-thiazolidin-5-ylidene}methyl)-1H-pyrrol-1-yl]benzoic acid	IC50	1890 nM
(E)-3-(5-methyl-2-furanyl)-N-[3-[[(E)-3-(5-methyl-2-furanyl)-1-oxoprop-2-enyl]amino]-4-nitrophenyl]-2-propenamide	IC50	2120 nM
(5E)-1-butyl-5-[(E)-3-(2-furanyl)prop-2-enylidene]-2-sulfanylidene-1,3-diazinane-4,6-dione	IC50	2180 nM
(E)-4-(1,3-benzothiazol-2-yl)-5-[4-(N-methylanilino)-3-nitro-phenyl]pent-4-enoic acid	IC50	2270 nM
(E)-4-(1,3-benzothiazol-2-yl)-5-[4-[2-(2,6-dichloroanilino)-2-oxoethoxy]-3-methoxyphenyl]-4-pentenoic acid	IC50	2300 nM
(8S)-3-[3-[(2-methyl-1-oxoprop-2-enyl)amino]phenyl]-7-[(2E,4E)-1-oxohexa-2,4-dienyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-8-carboxamide	IC50	2300 nM
6-[(5E)-4-keto-5-[[1-phenyl-3-(2-thienyl)pyrazol-4-yl]methylene]-2-thioxo-thiazolidin-3-yl]hexanoic acid	IC50	2310 nM
1,8,9-TRIHYDROXYANTHRACENE	IC50	2390 nM
(3aR,6aS)-3-(2-chlorophenyl)-5-(2,5-dimethoxyphenyl)-3a,6a-dihydropyrrol[3,4-d]isoxazole-4,6-quinone	IC50	2490 nM
2-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-4-(3-ethoxy-4-hydroxybenzylidene)-5-phenyl-2,4-dihydro-3H-pyrazol-3-one	IC50	2540 nM
SMR000715476	IC50	2550 nM
4-({[4-(2-fluorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]sulfonyl}amino)benzoic acid	IC50	2580 nM
N-[2-(dimethylamino)-2-phenylethyl]-2-(furan-2-yl)quinoline-4-carboxamide	IC50	2750 nM
SMR000542887	EC50	3050 nM
(8S)-3-(3-methacrylamidophenyl)-7-methacryloyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-8-carboxamide	IC50	3080 nM
2-[4-[[5-(4-chlorophenyl)-6-ethoxycarbonyl-7-methyl-3-oxidanylidene-5H-[1,3]thiazolo[3,2-a]pyrimidin-2-ylidene]methyl]phenoxy]ethanoic acid	IC50	3200 nM
2-[[4-[(2E)-2-[(5-bromanyl-2-methoxy-phenyl)methylidene]hydrazinyl]-3-nitro-phenyl]sulfonylamino]benzoic acid	IC50	3390 nM
4-[2-[(E)-(2,5-diketo-1-phenyl-imidazolidin-4-ylidene)methyl]pyrrol-1-yl]benzoic acid	IC50	3510 nM
(5Z)-3-(4-chlorobenzyl)-5-(4-hydroxy-3-methoxy-5-nitro-benzylidene)thiazolidine-2,4-quinone	IC50	3540 nM
(5E)-5-[[4-(4-methylphenyl)-2-thiophen-2-yl-4H-1-benzopyran-3-yl]methylidene]-2-sulfanylidene-4-thiazolidinone	IC50	3630 nM
cid_659329	IC50	3670 nM
4-[8-[(3-methoxyphenyl)sulfamoyl]-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl]benzoic acid	EC50	3880 nM
(6E)-2-(ethylsulfonyl)-6-({5-[(2-furylmethyl)thio]-2-furyl}methylene)-5-imino-5,6-dihydro-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-one	IC50	3960 nM
SMR000620617	IC50	4040 nM

ChEMBL bioactivities

408 potent at pChembl≥5 of 517 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.52	IC50	0.3	nM	CHEMBL3087498
8.74	IC50	1.8	nM	CHEMBL6163134
8.54	IC50	2.9	nM	CHEMBL2171169
7.73	IC50	18.6	nM	PSAMMAPLIN A
7.68	IC50	21	nM	CHEMBL4215326
7.57	IC50	27	nM	CHEMBL5279012
7.52	IC50	30	nM	DECITABINE
7.50	IC50	32	nM	CHEMBL4208004
7.40	IC50	40	nM	CHEMBL4212905
7.40	EC50	40	nM	CHEMBL5613516
7.21	IC50	61	nM	CHEMBL5613516
7.15	IC50	71	nM	S-ADENOSYLHOMOCYSTEINE
7.14	IC50	73	nM	CHEMBL4208010
7.10	IC50	80	nM	CHEMBL4211688
7.08	IC50	83	nM	CHEMBL4203133
7.08	IC50	83	nM	CHEMBL4215862
6.94	IC50	115	nM	CHEMBL1564869
6.92	IC50	120	nM	CHEMBL3126646
6.91	IC50	123	nM	CHEMBL4208812
6.90	Kd	127	nM	CHEMBL5591775
6.86	IC50	137	nM	CHEMBL4163329
6.85	IC50	140	nM	CHEMBL4206035
6.84	Kd	145	nM	CHEMBL5584171
6.82	IC50	150	nM	CHEMBL4588797
6.80	Kd	160	nM	CHEMBL5592841
6.78	IC50	167	nM	CHEMBL4856184
6.74	Kd	183	nM	CHEMBL5595428
6.73	IC50	187	nM	CHEMBL4216593
6.70	IC50	201	nM	CHEMBL4216144
6.70	IC50	200	nM	CHEMBL4213346
6.70	IC50	200	nM	S-ADENOSYLHOMOCYSTEINE
6.69	IC50	205	nM	CHEMBL4203647
6.68	IC50	211	nM	CHEMBL4204482
6.67	IC50	212	nM	CHEMBL4205136
6.66	IC50	220	nM	CHEMBL4203933
6.64	IC50	230	nM	CHEMBL4159597
6.64	IC50	231	nM	CHEMBL4171233
6.64	IC50	230	nM	CHEMBL5723367
6.63	IC50	232	nM	CHEMBL4170225
6.63	IC50	234	nM	CHEMBL4160008
6.63	IC50	235	nM	CHEMBL4207331
6.63	IC50	234	nM	CHEMBL4205373
6.61	IC50	247	nM	CHEMBL4210033
6.60	IC50	250	nM	CHEMBL4204903
6.58	IC50	261	nM	CHEMBL4216663
6.57	IC50	267	nM	CHEMBL4870578
6.56	IC50	274	nM	CHEMBL4176464
6.55	IC50	284	nM	CHEMBL4173626
6.54	IC50	290	nM	CHEMBL4212218
6.54	IC50	288	nM	S-ADENOSYLHOMOCYSTEINE

PubChem BioAssay actives

215 with measured affinity, of 956 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-[3-[[(2R,3S,4R,5R)-5-(4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methyl-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea	1636910: Inhibition of DNMT1 (unknown origin)	ic50	0.0003	uM
1-[3-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea	1636910: Inhibition of DNMT1 (unknown origin)	ic50	0.0029	uM
(2E)-3-(3-bromo-4-hydroxyphenyl)-N-[2-[2-[[(2E)-3-(3-bromo-4-hydroxyphenyl)-2-hydroxyiminopropanoyl]amino]ethyldisulfanyl]ethyl]-2-hydroxyiminopropanamide	670039: Inhibition of semi-purified DNMT1	ic50	0.0186	uM
6-methoxy-7-[(2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy]-2-(5-methylfuran-2-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.0210	uM
decitabine	1505769: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.0300	uM
6-methoxy-2-(5-methylfuran-2-yl)-N-[(1-methylpiperidin-4-yl)methyl]-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.0320	uM
2-(5-ethylfuran-2-yl)-6-methoxy-N-[(1-methylpiperidin-4-yl)methyl]-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.0400	uM
2-[[6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethyl-2-pyridinyl]sulfanyl]-2-phenylacetamide	2127264: Inhibition of NLuc-fused DNMT1 expressed hypomorphic in human HCT-116 cells assessed as TSG repoter activation at 3 uM incubated for 72 hrs by Nano-Glo Luciferase assay	ec50	0.0400	uM
(2S)-2-amino-4-[[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]butanoic acid	1689505: Inhibition of recombinant human DNMT1 using poly(dl-dC) as substrate by hotspot assay	ic50	0.0710	uM
6-methoxy-2-(5-methylfuran-2-yl)-N-(1-methylpiperidin-4-yl)-7-(piperidin-4-ylmethoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.0730	uM
2-(5-ethylfuran-2-yl)-6-methoxy-N-[(3-methyl-3-azabicyclo[3.2.1]octan-8-yl)methyl]-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.0800	uM
6-methoxy-2-(5-methylfuran-2-yl)-N-(1-methylpiperidin-4-yl)-7-[(1-methylpiperidin-4-yl)methoxy]quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.0830	uM
6-methoxy-2-(5-methylfuran-2-yl)-N-(1-methylpiperidin-4-yl)-7-[(2-propan-2-yl-2-azaspiro[3.3]heptan-6-yl)oxy]quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.0830	uM
(2S)-2-(1,3-dioxoisoindol-2-yl)-3-(1H-indol-3-yl)propanoic acid	1777442: Inhibition of DNMT (unknown origin) by densitometric analysis	ic50	0.1150	uM
N-[3-[(2-amino-6-methylpyrimidin-4-yl)amino]phenyl]-3-(quinolin-4-ylamino)benzamide	1073771: Inhibition of human N-terminal 600 residues-deleted DNMT1 using poly(dI-dC) as substrate in presence of AdoMet	ic50	0.1200	uM
6-methoxy-N-(7-methyl-7-azaspiro[3.5]nonan-3-yl)-2-(5-methylfuran-2-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.1230	uM
(2R)-2-(1,3-dioxoisoindol-2-yl)-3-(1,3,6-trichlorocarbazol-9-yl)propanoic acid	2115847: Binding affinity to human DNMT1 expressed in Escherichia coli assessed as equilibrium dissociation constant by SPR analysis	kd	0.1270	uM
6-methoxy-2-(5-methylfuran-2-yl)-N-piperidin-4-yl-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1505769: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.1370	uM
6-methoxy-N-(7-methyl-7-azaspiro[3.5]nonan-2-yl)-2-(5-methylfuran-2-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.1400	uM
3-(3,6-diiodocarbazol-9-yl)-2-(1,3-dioxoisoindol-2-yl)propanoic acid	2115847: Binding affinity to human DNMT1 expressed in Escherichia coli assessed as equilibrium dissociation constant by SPR analysis	kd	0.1450	uM
(2S)-2-amino-4-[[(2S,3S,4R,5R)-5-(4-amino-5-cyanopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfanyl]butanoic acid	1636910: Inhibition of DNMT1 (unknown origin)	ic50	0.1500	uM
2-(1,3-dioxoisoindol-2-yl)-3-(1,3,6-trichlorocarbazol-9-yl)propanoic acid	2115847: Binding affinity to human DNMT1 expressed in Escherichia coli assessed as equilibrium dissociation constant by SPR analysis	kd	0.1600	uM
N-hydroxy-4-[[4-[[[6-methoxy-2-(5-methylfuran-2-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-yl]amino]methyl]piperidin-1-yl]methyl]benzamide	1775568: Inhibition of human DNMT1 enzyme using polydeoxy-inosine polydeoxy-cytosine DNA as substrate incubated for 15 mins in presence of SAM by TR-FRET assay	ic50	0.1670	uM
(2S)-2-(1,3-dioxoisoindol-2-yl)-3-(1,3,6-trichlorocarbazol-9-yl)propanoic acid	2115847: Binding affinity to human DNMT1 expressed in Escherichia coli assessed as equilibrium dissociation constant by SPR analysis	kd	0.1830	uM
6-methoxy-7-[(2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy]-2-(5-methylfuran-2-yl)-N-(7-propan-2-yl-7-azaspiro[3.5]nonan-2-yl)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.1870	uM
6-methoxy-N-(7-methyl-7-azaspiro[3.5]nonan-2-yl)-2-(5-methylfuran-2-yl)-7-[(1-methylpiperidin-4-yl)methoxy]quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2000	uM
6-methoxy-N-(6-methyl-6-azaspiro[3.4]octan-2-yl)-2-(5-methylfuran-2-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2010	uM
6-methoxy-2-(5-methylfuran-2-yl)-N-[(1-propan-2-ylpiperidin-4-yl)methyl]-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2050	uM
6-methoxy-2-(5-methylfuran-2-yl)-N-(7-propan-2-yl-7-azaspiro[3.5]nonan-2-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2110	uM
7-[3-(5-azaspiro[2.4]heptan-5-yl)propoxy]-2-(5-ethylfuran-2-yl)-6-methoxy-N-(1-methylpiperidin-4-yl)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2120	uM
2-(5-ethylfuran-2-yl)-6-methoxy-N-(7-methyl-7-azaspiro[3.5]nonan-3-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2200	uM
6-methoxy-N-(1-methylpiperidin-4-yl)-2-(5-methylthiophen-2-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1505769: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2300	uM
6-methoxy-2-(5-methylfuran-2-yl)-N-(1-propan-2-ylpiperidin-4-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1505769: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2310	uM
6-methoxy-N-(1-methylpiperidin-4-yl)-2-(5-methyl-1H-pyrrol-2-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1505769: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2320	uM
2-(5-ethylfuran-2-yl)-6-methoxy-N-(1-methylpiperidin-4-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2340	uM
6-methoxy-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(5-methylfuran-2-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2340	uM
6-methoxy-N-(3-methyl-3-azabicyclo[3.2.1]octan-8-yl)-2-(5-methylfuran-2-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2350	uM
2-(5-ethylfuran-2-yl)-6-methoxy-N-(1-methylpiperidin-4-yl)-7-(3-piperidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2470	uM
6-methoxy-7-[(2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy]-N-(7-methyl-7-azaspiro[3.5]nonan-2-yl)-2-(5-methylfuran-2-yl)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2500	uM
6-methoxy-N-[(3-methyl-3-azabicyclo[3.2.1]octan-8-yl)methyl]-2-(5-methylfuran-2-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2610	uM
4-[[4-[[[6,7-dimethoxy-2-(5-methylfuran-2-yl)quinolin-4-yl]amino]methyl]piperidin-1-yl]methyl]-N-hydroxybenzamide	1775568: Inhibition of human DNMT1 enzyme using polydeoxy-inosine polydeoxy-cytosine DNA as substrate incubated for 15 mins in presence of SAM by TR-FRET assay	ic50	0.2670	uM
N-(1-cyclopropylpiperidin-4-yl)-2-(5-ethylfuran-2-yl)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1505769: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2740	uM
2-(5-ethylfuran-2-yl)-6-methoxy-N-(1-propan-2-ylpiperidin-4-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1505769: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2840	uM
6-methoxy-N-(6-methyl-6-azaspiro[3.4]octan-3-yl)-2-(5-methylfuran-2-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2900	uM
4-[[6-methoxy-2-(5-methylfuran-2-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-yl]amino]-1-methylpiperidin-2-one	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2970	uM
6-chloro-2-(5-methylfuran-2-yl)-N-(1-methylpiperidin-4-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-amine	1381131: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.2980	uM
7-[5-(2-acetamidoethyl)-2-hydroxyphenyl]-3,5,6,8-tetrahydroxy-9,10-dioxoanthracene-1,2-dicarboxylic acid	2037687: Competitive inhibition of DNMT1 (unknown origin)	ki	0.3000	uM
azacitidine	1505769: Inhibition of human DNMT1 using polydeoxyinosine polydeoxycytosine DNA as substrate after 15 mins in presence of SAM by TR-FRET assay	ic50	0.3000	uM
N-hydroxy-4-[[4-[[6-methoxy-2-(5-methylfuran-2-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinolin-4-yl]amino]piperidin-1-yl]methyl]benzamide	1775568: Inhibition of human DNMT1 enzyme using polydeoxy-inosine polydeoxy-cytosine DNA as substrate incubated for 15 mins in presence of SAM by TR-FRET assay	ic50	0.3180	uM
5-[[4-[[[6,7-dimethoxy-2-(5-methylfuran-2-yl)quinolin-4-yl]amino]methyl]piperidin-1-yl]methyl]-N-hydroxythiophene-2-carboxamide	1775568: Inhibition of human DNMT1 enzyme using polydeoxy-inosine polydeoxy-cytosine DNA as substrate incubated for 15 mins in presence of SAM by TR-FRET assay	ic50	0.3230	uM

CTD chemical–gene interactions

172 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Decitabine	affects expression, affects cotreatment, decreases expression, increases expression, affects reaction (+3 more)	22
sodium arsenite	decreases reaction, increases expression, affects cotreatment, decreases expression, affects localization (+4 more)	14
bisphenol A	decreases methylation, increases expression, increases methylation, decreases reaction, affects cotreatment (+4 more)	11
Arsenic Trioxide	affects binding, decreases reaction, decreases expression, increases reaction, decreases activity (+1 more)	11
Resveratrol	increases expression, decreases expression, affects binding, decreases reaction, increases reaction (+1 more)	8
Arsenic	affects methylation, decreases expression, increases expression, affects response to substance, decreases reaction (+1 more)	7
Estradiol	decreases phosphorylation, increases expression, affects binding, decreases reaction, increases reaction (+2 more)	6
hydroquinone	affects expression, decreases expression, increases expression	5
epigallocatechin gallate	decreases activity, decreases reaction, increases expression, increases reaction, affects binding	4
Folic Acid	decreases expression, decreases reaction, increases expression, affects expression, affects reaction	4
Hydrogen Peroxide	decreases reaction, affects cotreatment, increases expression, increases methylation, decreases response to substance (+1 more)	4
Quercetin	increases reaction, affects cotreatment, decreases activity, decreases expression, increases expression (+1 more)	4
Cadmium Chloride	increases expression, affects cotreatment, increases methylation, decreases reaction, decreases expression (+1 more)	4
Genistein	decreases expression, increases expression, decreases reaction	4
Particulate Matter	affects binding, decreases reaction, increases abundance, decreases expression	4
Fulvestrant	affects cotreatment, decreases expression, decreases reaction, increases expression	3
Acetylcysteine	affects cotreatment, increases expression, increases methylation, decreases reaction, affects binding (+2 more)	3
Azacitidine	decreases expression, increases reaction, affects binding, decreases reaction, increases uptake	3
Benzo(a)pyrene	increases degradation, increases expression, increases methylation, decreases reaction	3
Doxorubicin	increases expression, increases reaction, decreases activity, decreases expression, affects response to substance (+2 more)	3
Tetrachlorodibenzodioxin	affects binding, affects cotreatment, increases reaction, decreases reaction	3
sulforaphane	decreases reaction, increases expression, decreases expression	2
fisetin	affects cotreatment, decreases activity, decreases expression	2
arsenic disulfide	decreases expression, increases expression	2
bisphenol S	decreases abundance, decreases expression, increases methylation, affects binding, increases reaction (+1 more)	2
SGI-1027	decreases activity, decreases expression, increases reaction	2
8-Hydroxy-2’-Deoxyguanosine	decreases activity, affects abundance	2
Glyphosate	increases expression	2
Vehicle Emissions	decreases reaction, increases abundance, decreases expression, increases expression, affects binding	2
Cadmium	increases expression, decreases reaction, affects response to substance	2

ChEMBL screening assays

233 unique, capped per target: 229 binding, 3 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1001551	Binding	Inhibition of DNMT1 assessed as drug level causing inhibition by SPA	DNA methyl transferase inhibiting halogenated monoterpenes from the Madagascar red marine alga Portieria hornemannii. — J Nat Prod
CHEMBL1963910	Functional	PUBCHEM_BIOASSAY: Dose response confirmation of DNMT1 inhibitors in a Fluorescent Molecular Beacon assay. (Class of assay: confirmatory)	PubChem BioAssay data set
CHEMBL4275456	ADMET	Inhibition of human DNMT1A using double-stranded hemi-DNA oligonucleotide as substrate measured after 40 mins by [3H]methyl incorporation assay	Design, synthesis and in vitro anti-Zika virus evaluation of novel Sinefungin derivatives. — Eur J Med Chem

Cellosaurus cell lines

14 cell lines: 11 cancer cell line, 3 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A7NI	2XSB	Cancer cell line	Female
CVCL_B8ES	Abcam HCT 116 DNMT1 KO	Cancer cell line	Male
CVCL_B8UW	Abcam MCF-7 DNMT1 KO	Cancer cell line	Female
CVCL_D5I8	HepG2-DP	Cancer cell line	Male
CVCL_E4U1	KOLF2.1J DNMT1 46.7kbdel DEL/WT	Induced pluripotent stem cell	Male
CVCL_E5EU	HCT 116 DNMT1(-/-)	Cancer cell line	Male
CVCL_E5EV	HCT 116 DNMT1(-/-) DNMT3B(-/-)	Cancer cell line	Male
CVCL_E5EW	HCT 116 DNMT1(-/-) DNMT3B(-/-) CDKN2A (R24fs*20/-)	Cancer cell line	Male
CVCL_E5EX	HCT 116 DNMT1(-/-) DNMT3B(-/-) retains methylation	Cancer cell line	Male
CVCL_E5EY	HCT 116 DNMT1(-/-) DNMT3B(-/-) CDKN2A (sil/-)	Cancer cell line	Male

Clinical trials (associated diseases)

249 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT00945009	PHASE3	ACTIVE_NOT_RECRUITING	Combination Chemotherapy and Surgery in Treating Young Patients With Wilms Tumor
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT01970098	PHASE3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	PHASE3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	PHASE3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	PHASE3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	PHASE3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT03901638	PHASE3	TERMINATED	Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy
NCT07040137	PHASE3	RECRUITING	Confirmatory Study 3 of KPS-0373 in Patients With Spinocerebellar Degeneration
NCT03783923	PHASE3	TERMINATED	A Study of Deflazacort (Emflaza®) in Participants With Limb-Girdle Muscular Dystrophy 2I (LGMD2I)
NCT06246513	PHASE3	ACTIVE_NOT_RECRUITING	A Trial to Learn More About an Experimental Gene Therapy Called Bidridistrogene Xeboparvovec (SRP-9003) as a Possible Treatment for Limb Girdle Muscular Dystrophy 2E/R4
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT00034242	PHASE2	COMPLETED	High-Dose Intravenous Immunoglobulin to Treat Cerebellar Degeneration
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
NCT00863538	PHASE2	COMPLETED	Phase II Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01004016	PHASE2	COMPLETED	A Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01350440	PHASE2	COMPLETED	Safety and Efficacy of Intravenous Immune Globulin in Treating Spinocerebellar Ataxia
NCT02540655	PHASE2	COMPLETED	Efficacy and Safety Study of Stemchymal® in Polyglutamine Spinocerebellar Ataxia
NCT03932669	PHASE2	COMPLETED	Effect of Nilotinib in Cerebellar Ataxia Patients
NCT04301284	PHASE2	WITHDRAWN	Study of CAD-1883 for Spinocerebellar Ataxia
NCT05125666	PHASE2	UNKNOWN	Efficacy of Dual Task Training on Children With Ataxia After Medulloblastoma Resection
NCT06397274	PHASE2	NOT_YET_RECRUITING	Stemchymal® for Polyglutamine Spinocerebellar Ataxia
NCT04054375	PHASE2	COMPLETED	Weekly Steroids in Muscular Dystrophy
NCT00683943	PHASE1	COMPLETED	Lithium Treatment for Patients With Spinocerebellar Ataxia Type I
NCT02287064	PHASE1	UNKNOWN	An Open-label Trial of Intravenous Immune Globulin (IVIG)in Treating Spinocerebellar Ataxias
NCT05157802	PHASE1	ACTIVE_NOT_RECRUITING	Promoting Physical Activity Engagement for People With Early-stage Cerebellar Ataxia
NCT00873782	PHASE1	COMPLETED	Safety Study of Transvenous Limb Perfusion in Human Muscular Dystrophy
NCT01344798	PHASE1	COMPLETED	Clinical Study of AAV1-gamma-sarcoglycan Gene Therapy for Limb Girdle Muscular Dystrophy Type 2C