CRY2

Summary

CRY2 (cryptochrome circadian regulator 2, HGNC:2385) is a protein-coding gene on chromosome 11p11.2, encoding Cryptochrome-2 (Q49AN0). Transcriptional repressor which forms a core component of the circadian clock.

This gene encodes a flavin adenine dinucleotide-binding protein that is a key component of the circadian core oscillator complex, which regulates the circadian clock. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene have been associated with altered sleep patterns. The encoded protein is widely conserved across plants and animals. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1408 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 96 total
• Druggable target: yes
• MANE Select transcript: NM_021117

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2385
Approved symbol	CRY2
Name	cryptochrome circadian regulator 2
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000121671
Ensembl biotype	protein_coding
OMIM	603732
Entrez	1408

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 12 protein_coding, 5 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000417225, ENST00000443527, ENST00000473199, ENST00000488962, ENST00000495237, ENST00000496571, ENST00000496667, ENST00000525110, ENST00000532390, ENST00000533779, ENST00000616080, ENST00000616623, ENST00000852822, ENST00000852823, ENST00000852824, ENST00000852825, ENST00000852826, ENST00000852827, ENST00000918213, ENST00000968514

RefSeq mRNA: 2 — MANE Select: NM_021117 NM_001127457, NM_021117

CCDS: CCDS44576, CCDS7915

Canonical transcript exons

ENST00000616080 — 12 exons

Exon	Start	End
ENSE00000824607	45870842	45870934
ENSE00000824608	45870330	45870532
ENSE00000824609	45870053	45870204
ENSE00000824610	45869506	45869817
ENSE00003501164	45872092	45872233
ENSE00003506499	45855982	45856090
ENSE00003640987	45858731	45858873
ENSE00003648876	45862060	45862148
ENSE00003653986	45867612	45867752
ENSE00003689007	45860848	45861032
ENSE00003712173	45880914	45883244
ENSE00003727077	45847475	45847705

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 95.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.1280 / max 258.8460, expressed in 1794 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114042	17.5384	1793
114044	0.4364	42
206265	0.0843	45
114043	0.0690	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	95.86	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.99	gold quality
skin of leg	UBERON:0001511	94.98	gold quality
cerebellar hemisphere	UBERON:0002245	94.87	gold quality
cerebellar cortex	UBERON:0002129	94.82	gold quality
muscle of leg	UBERON:0001383	94.71	gold quality
type B pancreatic cell	CL:0000169	94.64	gold quality
gastrocnemius	UBERON:0001388	94.64	gold quality
olfactory bulb	UBERON:0002264	94.63	gold quality
right lobe of liver	UBERON:0001114	94.41	gold quality
apex of heart	UBERON:0002098	94.07	gold quality
cerebellum	UBERON:0002037	94.04	gold quality
skin of abdomen	UBERON:0001416	93.94	gold quality
right frontal lobe	UBERON:0002810	93.79	gold quality
right atrium auricular region	UBERON:0006631	93.79	gold quality
cardiac atrium	UBERON:0002081	93.51	gold quality
muscle organ	UBERON:0001630	93.42	gold quality
nucleus accumbens	UBERON:0001882	93.28	gold quality
popliteal artery	UBERON:0002250	93.22	gold quality
tibial artery	UBERON:0007610	93.22	gold quality
adenohypophysis	UBERON:0002196	93.21	gold quality
right uterine tube	UBERON:0001302	92.97	gold quality
left ovary	UBERON:0002119	92.96	gold quality
heart left ventricle	UBERON:0002084	92.58	gold quality
zone of skin	UBERON:0000014	92.51	gold quality
lateral globus pallidus	UBERON:0002476	92.46	gold quality
cingulate cortex	UBERON:0003027	92.39	gold quality
cardiac ventricle	UBERON:0002082	92.34	gold quality
sural nerve	UBERON:0015488	92.31	gold quality
mucosa of stomach	UBERON:0001199	92.29	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BMAL1, CLOCK, NPAS2

miRNA regulators (miRDB)

116 targeting CRY2, 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-8485	100.00	77.57	4731
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-590-3P	99.96	74.34	6478
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-106A-5P	99.90	73.94	2683

Literature-anchored findings (GeneRIF, showing 40)

• CRY2 binds to DNA and in particular to single-stranded DNA with moderately high affinity and to DNA containing (6-4) photoproducts with higher affinity, but it has no DNA repair activity. (PMID:12627958)
• Transcripts of hCry2 underwent circadian oscillation. The expression profile of hCry2 was similar to that of hPer3. (PMID:14750904)
• The carboxyl-terminal domain of human cryptochrome 2 is intrinsically unstructured in solution, consistent with its presumed role as a signal transduction domain. (PMID:15751956)
• the CLOCK(NPAS2)/BMAL1 complex is post-translationally regulated by cry1 and cry2 (PMID:16628007)
• A clear circadian rhythm was shown for hPer1, hPer2, and hCry2 expression in CD34(+) cells and for hPer1 in the whole bone marrow, with maxima from early morning to midday. (PMID:17440215)
• The regulators of clock-controlled transcription PER2, CRY1 and CRY2 differ in their capacity to interact with each single component of the BMAL1-CLOCK heterodimer and, in the case of BMAL1, also in their interaction sites. (PMID:18430226)
• The expression level of CRY2 was decreased in hepatrocellular carcinoma. (PMID:18444243)
• Both genetic association and functional analyses suggest that the circadian gene CRY2 may play an important role in NHL development. (PMID:19318546)
• Data suggest that CRY2 locus is associated with vulnerability for depression. (PMID:20195522)
• findings suggest a role for CRY2 in breast tumorigenesis (PMID:20233903)
• Data suggest a limited, but potentially important role for CRY2 in the regulation of DNA damage repair and the maintenance of genomic stability in breast cancer. (PMID:20334671)
• CRY2 gene variation was associated with bipolar disorder. (PMID:20856823)
• Lean individuals exhibited significant (P < 0.05) temporal changes of core clock (PER1, PER2, PER3, CRY2, BMAL1, and DBP) and metabolic (REVERBalpha, RIP140, and PGC1alpha) genes. (PMID:21411511)
• Human CRY2 has the molecular capability to function as a light-sensitive magnetosensor. (PMID:21694704)
• the associations of GLIS3-rs7034200 and CRY2-rs11605924 with fasting glucose, beta cell function, and type 2 diabetes (PMID:21747906)
• Genetic variants of CRY2 associate with seasonal affective disorder or winter depression. (PMID:22538398)
• Reduced cry2 expression is associated with glioma. (PMID:23317246)
• These data document for the first time that the expression of BMAL1, PER3, PPARD and CRY2 genes is altered in gestational diabetes compared to normal pregnant women. deranged expression of clock genes may play a pathogenic role in GDM. (PMID:23323702)
• Studies indicate that in the cytoplasm, PER3 protein heterodimerizes with PER1, PER2, CRY1, and CRY2 proteins and enters into the nucleus, resulting in repression of CLOCK-BMAL1-mediated transcription. (PMID:23546644)
• Four CRY2 genetic variants (rs10838524, rs7121611, rs7945565, rs1401419) associated significantly with dysthymia (false discovery rate q<0.05). (PMID:23951166)
• CRY2 genetic variants associate with the depressive episodes in a range of mood disorder; CRY2 is hypothesized to a key to the resetting of clocks throughout and play a leading role in the antidepressant effect of total sleep deprivation (PMID:24099037)
• Our data indicate that variants in the circadian-related genes CRY2 and MTNR1B may affect long-term changes in energy expenditure, and dietary fat intake may modify the genetic effects. (PMID:24335056)
• CRY2 and REV-ERB ALPHA as the clock genes upregulated in obesity during the 24 h period and that REV-ERB ALPHA is an important gene associated with MS. (PMID:25365257)
• CRY1 and CRY2 variants showed nominal association with the metabolic syndrome components, hypertension and triglyceride levels. (PMID:25391456)
• these observations suggest a biologically plausible season-dependent association between SNPs at CRY1, CRY2 and MTNR1B and glucose homeostasis. (PMID:25707907)
• These findings suggest that the core circadian gene CRY2 is associated with breast cancer progression and prognosis, and that knockdown of CRY2 causes the epigenetic dysregulation of genes involved in cancer-relevant pathways (PMID:25740058)
• Data indicate that cryptochrome 2 (CRY2) knockdown leads to chemosensitivity of colorectal cancer cell lines. (PMID:25855785)
• For the first time, we show that Cry 2 rs2292910 and MTNR1B rs3781638 are associated with osteoporosis in a Chinese geriatric cohort. (PMID:26564225)
• data may point to CRY2 as a novel switch in hepatic fuel metabolism promoting triglyceride storage and, concomitantly, limiting glucose production (PMID:26726810)
• Altered CRY1 and CRY2 expression patterns and the interplay with the genetic landscape in colon cancer cells may underlie phenotypic divergence. (PMID:26768731)
• Given the distinct characteristics of the C-terminal tails of the CRY1 and CRY2 proteins, our study addresses a long-standing hypothesis that the ratio of these two CRY molecules affects the clock period. (PMID:26966073)
• The present study identified USP7 and TDP-43 as the regulators of CRY1 and CRY2, underscoring the significance of the stability control process of CRY proteins for period determination in the mammalian circadian clockwork. (PMID:27123980)
• In the longitudinal analysis, CRY2 SNP rs61884508 was protective from worsening of problematicity of seasonal variations of mood disorder. In the cross-sectional analysis, CRY2 SNP rs72902437 showed evidence of association with problematicity of seasonal variations, as did SNP rs1554338 (in the MAPK8IP1 and downstream of CRY2). (PMID:27267441)
• These results demonstrate that CRY2 stability controlled by FBXL3 plays a key role in the regulation of human sleep wake behavior. (PMID:27529127)
• The earlier reported association of CRY2 variants with dysthymia was confirmed and extended to major depressive disorder. (PMID:27721187)
• CRY2 and FBXL3 cooperatively degrade c-MYC preventing the development of cancer. (PMID:27840026)
• The FOXM1 is a negative regulator of CRY2 in breast cancer via enhancing methylation in CRY2 promoter and its high expression is an independent predictor of favorable MR-free survival in ER+ breast cancer patients. (PMID:28579430)
• data indicate an oncogenic role of miR-181d in CRC by promoting glycolysis, and miR-181d/CRY2/FBXL3/c-myc feedback loop might be a therapeutic target for patients with CRC. (PMID:28749470)
• CRY1/2 serve as corepressors for many NRs. (PMID:28751364)
• CRY2 levels (ng/mL) were markedly higher in both Metabolic syndrome (MetS) groups (non-diabetic and pre-diabetic/diabetic) (all with p-value < 0.001). A reciprocal melatonin-CRY2 relationship was observed in the MetS (non-diabetic) group (p-value = 0.003). (PMID:29813030)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cry2	ENSDARG00000102403
mus_musculus	Cry2	ENSMUSG00000068742
rattus_norvegicus	Cry2	ENSRNOG00000007478

Paralogs (1): CRY1 (ENSG00000008405)

Protein

Protein identifiers

Cryptochrome-2 — Q49AN0 (reviewed: Q49AN0)

All UniProt accessions (3): A0A0D2X7Z3, A2I2P1, Q49AN0

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots ‘circa’ (about) and ‘diem’ (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for ’timegivers’). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5’-CACGTG-3’) within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. CRY1 and CRY2 have redundant functions but also differential and selective contributions at least in defining the pace of the SCN circadian clock and its circadian transcriptional outputs. Less potent transcriptional repressor in cerebellum and liver than CRY1, though less effective in lengthening the period of the SCN oscillator. Seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY1, dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. May mediate circadian regulation of cAMP signaling and gluconeogenesis by blocking glucagon-mediated increases in intracellular cAMP concentrations and in CREB1 phosphorylation. Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Plays a key role in glucose and lipid metabolism modulation, in part, through the transcriptional regulation of genes involved in these pathways, such as LEP or ACSL4. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). Represses the CLOCK-BMAL1 induced transcription of BHLHE40/DEC1. Represses the CLOCK-BMAL1 induced transcription of NAMPT. Represses PPARD and its target genes in the skeletal muscle and limits exercise capacity. Represses the transcriptional activity of NR1I2.

Subunit / interactions. Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins. Interacts with TIMELESS. Interacts directly with PER1, PER2 and PER3; interaction with PER2 inhibits its ubiquitination and vice versa. Interacts with CLOCK-BMAL1. Interacts with CLOCK. Interacts with BMAL1. Interacts with NFIL3. Interacts with FBXL3. Interacts with FBXL21. FBXL3, PER2 and the cofactor FAD compete for overlapping binding sites. FBXL3 cannot bind CRY2 that interacts already with PER2 or that contains bound FAD. Interacts with PPP5C (via TPR repeats); the interaction down-regulates the PPP5C phosphatase activity on CSNK1E. Interacts with nuclear receptors AR and NR3C1/GR; the interaction is ligand dependent. Interacts with PRKDC and CIART. Interacts with ISCA1 (in vitro). Interacts with DDB1, USP7 and TARDBP. Interacts with HNF4A. Interacts with PPARA. Interacts with PPARD (via domain NR LBD) and NR1I2 (via domain NR LBD) in a ligand-dependent manner. Interacts with PPARG, NR1I3 and VDR in a ligand-dependent manner.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in all tissues examined including fetal brain, fibroblasts, heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and leukocytes. Highest levels in heart and skeletal muscle.

Post-translational modifications. Phosphorylation on Ser-266 by MAPK is important for the inhibition of CLOCK-BMAL1-mediated transcriptional activity. Phosphorylation by CSKNE requires interaction with PER1 or PER2. Phosphorylated in a circadian manner at Ser-554 and Ser-558 in the suprachiasmatic nucleus (SCN) and liver. Phosphorylation at Ser-558 by DYRK1A promotes subsequent phosphorylation at Ser-554 by GSK3-beta: the two-step phosphorylation at the neighboring Ser residues leads to its proteasomal degradation. Ubiquitinated by the SCF(FBXL3) and SCF(FBXL21) complexes, regulating the balance between degradation and stabilization. The SCF(FBXL3) complex is mainly nuclear and mediates ubiquitination and subsequent degradation of CRY2. In contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads to stabilize CRY2 and counteract the activity of the SCF(FBXL3) complex. The SCF(FBXL3) and SCF(FBXL21) complexes probably mediate ubiquitination at different Lys residues. The SCF(FBXL3) complex recognizes and binds CRY2 phosphorylated at Ser-554 and Ser-558. Ubiquitination may be inhibited by PER2. Deubiquitinated by USP7.

Activity regulation. KL001 (N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-N-(2-furanylmethyl)-methanesulfonamide) binds to CRY1 and stabilizes it by inhibiting FBXL3- and ubiquitin-dependent degradation of CRY1 resulting in lengthening of the circadian periods.

Cofactor. Binds 1 FAD per subunit. Only a minority of the protein molecules contain bound FAD. Contrary to the situation in photolyases, the FAD is bound in a shallow, surface-exposed pocket. Binds 1 5,10-methenyltetrahydrofolate (MTHF) non-covalently per subunit.

Similarity. Belongs to the DNA photolyase class-1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q49AN0-1	1	yes
Q49AN0-2	2

RefSeq proteins (2): NP_001120929, NP_066940* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002081	Cryptochrome/DNA_photolyase_1	Family
IPR005101	Cryptochr/Photolyase_FAD-bd	Domain
IPR006050	DNA_photolyase_N	Domain
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR036134	Crypto/Photolyase_FAD-like_sf	Homologous_superfamily
IPR036155	Crypto/Photolyase_N_sf	Homologous_superfamily

Pfam: PF00875, PF03441

UniProt features (23 total): cross-link 6, modified residue 5, binding site 4, region of interest 2, sequence conflict 2, chain 1, domain 1, splice variant 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q49AN0-F1	85.42	0.74

Functional residue map

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

Ligand- & substrate-binding residues (4): 271; 308; 374; 406–408

Post-translational modifications (11): 266, 299, 554, 558, 30, 126, 242, 348, 475, 504, 90

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9931510	Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes
R-HSA-9931521	The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex
R-HSA-9931530	Phosphorylation and nuclear translocation of the CRY:PER:kinase complex
R-HSA-9932298	Degradation of CRY and PER proteins
R-HSA-9931512	Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters

MSigDB gene sets: 281 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_PHOTOPERIODISM, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, GOBP_CIRCADIAN_REGULATION_OF_GENE_EXPRESSION, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, KAUFFMANN_DNA_REPAIR_GENES

GO Biological Process (18): negative regulation of transcription by RNA polymerase II (GO:0000122), protein import into nucleus (GO:0006606), circadian rhythm (GO:0007623), response to light stimulus (GO:0009416), blue light signaling pathway (GO:0009785), response to activity (GO:0014823), lipid storage (GO:0019915), response to insulin (GO:0032868), circadian regulation of gene expression (GO:0032922), glucose homeostasis (GO:0042593), regulation of circadian rhythm (GO:0042752), negative regulation of circadian rhythm (GO:0042754), entrainment of circadian clock by photoperiod (GO:0043153), negative regulation of DNA-templated transcription (GO:0045892), regulation of sodium-dependent phosphate transport (GO:2000118), negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway (GO:2000323), negative regulation of glucocorticoid secretion (GO:2000850), rhythmic process (GO:0048511)

GO Molecular Function (15): transcription cis-regulatory region binding (GO:0000976), DNA binding (GO:0003677), damaged DNA binding (GO:0003684), single-stranded DNA binding (GO:0003697), protein phosphatase inhibitor activity (GO:0004864), blue light photoreceptor activity (GO:0009882), nuclear receptor binding (GO:0016922), protein kinase binding (GO:0019901), phosphatase binding (GO:0019902), FAD binding (GO:0071949), nucleotide binding (GO:0000166), protein binding (GO:0005515), photoreceptor activity (GO:0009881), lyase activity (GO:0016829), kinase binding (GO:0019900)

GO Cellular Component (7): extracellular region (GO:0005576), nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), nuclear speck (GO:0016607), Cry-Per complex (GO:1990512)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Circadian clock	5

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
circadian rhythm	3
cellular anatomical structure	3
DNA binding	2
enzyme binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
rhythmic process	1
response to radiation	1
intracellular receptor signaling pathway	1
cellular response to blue light	1
response to stimulus	1
nutrient storage	1
response to peptide hormone	1
regulation of gene expression	1
carbohydrate homeostasis	1
regulation of biological process	1
regulation of circadian rhythm	1
negative regulation of biological process	1
photoperiodism	1
entrainment of circadian clock	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
regulation of phosphate transport	1
sodium-dependent phosphate transport	1
negative regulation of intracellular steroid hormone receptor signaling pathway	1
nuclear receptor-mediated glucocorticoid signaling pathway	1
regulation of nuclear receptor-mediated glucocorticoid signaling pathway	1
glucocorticoid secretion	1
negative regulation of corticosteroid hormone secretion	1
regulation of glucocorticoid secretion	1
biological_process	1
transcription regulatory region nucleic acid binding	1

Protein interactions and networks

STRING

2197 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRY2	PER2	O15055	998
CRY2	CIB1	Q99828	996
CRY2	TIMELESS	Q9UNS1	993
CRY2	CLOCK	O15516	984
CRY2	PER3	P56645	984
CRY2	BMAL1	O00327	983
CRY2	FBXL3	Q9UKT7	981
CRY2	CSNK1E	P49674	961
CRY2	NPAS2	Q99743	953
CRY2	NR1D1	P20393	947
CRY2	BHLHE41	Q9C0J9	916
CRY2	NR1D2	Q14995	897
CRY2	A0A087WZY1	A0A087WZY1	891
CRY2	PRH1	P02810	885
CRY2	NFIL3	Q16649	859

IntAct

142 interactions, top by confidence:

A	B	Type	Score
CSNK1E	PER2	psi-mi:“MI:0914”(association)	0.850
CSNK1E	PER1	psi-mi:“MI:0914”(association)	0.840
CSNK1D	PER2	psi-mi:“MI:0914”(association)	0.810
CRY2	CSNK1E	psi-mi:“MI:0914”(association)	0.640
FBXL3	CRY1	psi-mi:“MI:0914”(association)	0.640
CRY2	SKP1	psi-mi:“MI:0914”(association)	0.640
QPRT	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
CRY1	CUL1	psi-mi:“MI:0914”(association)	0.640
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
CRY2	PDE9A	psi-mi:“MI:0915”(physical association)	0.560
CTBP1	CRY2	psi-mi:“MI:0915”(physical association)	0.560
CRY2	MTUS2	psi-mi:“MI:0915”(physical association)	0.560
MTUS2	CRY2	psi-mi:“MI:0915”(physical association)	0.560
CRY2	CTBP1	psi-mi:“MI:0915”(physical association)	0.560
PDE9A	CRY2	psi-mi:“MI:0915”(physical association)	0.560
SBK3	CRY2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	CRY2	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	CRY2	psi-mi:“MI:0915”(physical association)	0.560
TRAF1	CRY2	psi-mi:“MI:0915”(physical association)	0.560
CRY2	KRTAP5-2	psi-mi:“MI:0915”(physical association)	0.560
CRY2	KRT40	psi-mi:“MI:0915”(physical association)	0.560
NADK	CRY2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (250): CTBP1 (Two-hybrid), PDE9A (Two-hybrid), MTUS2 (Two-hybrid), CRY2 (Affinity Capture-RNA), BRCA1 (Two-hybrid), CRY2 (Two-hybrid), CRY2 (Two-hybrid), DEC1 (Two-hybrid), BHLHE41 (Two-hybrid), PER1 (Two-hybrid), PER2 (Two-hybrid), PPP2R5D (Two-hybrid), PPP2R1B (Two-hybrid), PPP2R5E (Two-hybrid), EZH2 (Two-hybrid)

ESM2 similar proteins: A2ARP1, A2RSY6, A4QNR3, A5D7S3, A6H8I2, A7Z050, B0WRR9, O48652, O77059, P0C644, P34205, P41229, P41230, P97784, Q01433, Q02356, Q0E2Y1, Q16526, Q17DK5, Q17QN2, Q293P8, Q2KI13, Q32Q86, Q38JA7, Q43125, Q49AN0, Q5IZC5, Q5RDF1, Q6P6R7, Q6PFW1, Q6ZZY0, Q70AD6, Q7PYI7, Q7T2D0, Q8BHD8, Q8QG60, Q8QG61, Q8R0P8, Q8VCZ6, Q8VEG4

Diamond homologs: A9CJC9, B0WRR9, O48652, P00914, P05327, P12768, P25078, P27526, P40115, P57386, P61496, P61497, P77967, Q04449, Q05380, Q0E2Y1, Q3IPX9, Q43125, Q49AN0, Q4I1Q6, Q4KML2, Q55081, Q75WS4, Q7NMD1, Q7SI68, Q7UJB1, Q89AJ9, Q923I8, Q96524, Q9HQ46, Q9KNA8, Q9R194, O77059, P97784, Q16526, Q17DK5, Q293P8, Q32Q86, Q38JU2, Q5IZC5

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
BMAL1/NPAS2	“up-regulates quantity by expression”	CRY2	“transcriptional regulation”
CRY2	“down-regulates activity”	BMAL1/NPAS2	binding
CRY2	“down-regulates activity”	CLOCK/BMAL1	binding
FBXL3	“down-regulates quantity by destabilization”	CRY2	binding
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	CRY2	polyubiquitination
ARNTL	“up-regulates quantity by expression”	CRY2	“transcriptional regulation”
CLOCK	“up-regulates quantity by expression”	CRY2	“transcriptional regulation”
CLOCK/BMAL1	“up-regulates quantity by expression”	CRY2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 65 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
The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex	7	108.6×	3e-11
Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes	6	62.1×	3e-08
Degradation of CRY and PER proteins	7	33.4×	5e-08
Keratinization	13	15.7×	1e-10

GO biological processes:

GO term	Partners	Fold	FDR
entrainment of circadian clock by photoperiod	6	87.9×	7e-09
regulation of circadian rhythm	9	46.7×	1e-10
circadian regulation of gene expression	9	42.1×	1e-10
circadian rhythm	6	29.3×	6e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	83
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1924 predictions. Top by Δscore:

Variant	Effect	Δscore
11:45855977:CACA:C	acceptor_loss	1.0000
11:45855979:CAGGT:C	acceptor_loss	1.0000
11:45856089:AGGTA:A	donor_loss	1.0000
11:45856090:GGTA:G	donor_loss	1.0000
11:45856092:T:G	donor_loss	1.0000
11:45858726:CACAG:C	acceptor_loss	1.0000
11:45858728:CAGG:C	acceptor_loss	1.0000
11:45858729:AGG:A	acceptor_loss	1.0000
11:45858730:G:GA	acceptor_loss	1.0000
11:45858730:GGAAT:G	acceptor_gain	1.0000
11:45858826:TGTGG:T	donor_gain	1.0000
11:45858830:G:GT	donor_gain	1.0000
11:45858869:GACAG:G	donor_gain	1.0000
11:45858873:GGTAA:G	donor_loss	1.0000
11:45858874:G:GA	donor_loss	1.0000
11:45858874:G:GG	donor_gain	1.0000
11:45858875:T:G	donor_loss	1.0000
11:45861028:GCTGG:G	donor_gain	1.0000
11:45861031:GG:G	donor_gain	1.0000
11:45861032:GG:G	donor_gain	1.0000
11:45861033:G:GG	donor_gain	1.0000
11:45867608:GTA:G	acceptor_loss	1.0000
11:45867609:TAGG:T	acceptor_loss	1.0000
11:45867610:A:AG	acceptor_gain	1.0000
11:45867610:A:T	acceptor_loss	1.0000
11:45867610:AG:A	acceptor_gain	1.0000
11:45867611:G:GA	acceptor_loss	1.0000
11:45867611:G:GG	acceptor_gain	1.0000
11:45867611:GG:G	acceptor_gain	1.0000
11:45867611:GGCCT:G	acceptor_gain	1.0000

AlphaMissense

3864 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:45867681:A:C	S271R	1.000
11:45867683:C:A	S271R	1.000
11:45867683:C:G	S271R	1.000
11:45869558:G:C	R312P	1.000
11:45869638:T:A	W339R	1.000
11:45869638:T:C	W339R	1.000
11:45869668:T:A	W349R	1.000
11:45869668:T:C	W349R	1.000
11:45869687:G:A	G355D	1.000
11:45869720:T:C	L366P	1.000
11:45869734:T:A	W371R	1.000
11:45869734:T:C	W371R	1.000
11:45869800:T:A	W393R	1.000
11:45869800:T:C	W393R	1.000
11:45870104:T:A	W416R	1.000
11:45870104:T:C	W416R	1.000
11:45870117:C:T	S420F	1.000
11:45870122:A:C	S422R	1.000
11:45870124:T:A	S422R	1.000
11:45870124:T:G	S422R	1.000
11:45870171:G:A	G438D	1.000
11:45870488:G:C	R502P	1.000
11:45847569:T:A	W27R	0.999
11:45847569:T:C	W27R	0.999
11:45855983:T:C	F73L	0.999
11:45855984:T:C	F73S	0.999
11:45855985:C:A	F73L	0.999
11:45855985:C:G	F73L	0.999
11:45860885:T:G	Y169D	0.999
11:45860895:T:C	F172S	0.999

dbSNP variants (sampled 300 via entrez): RS1000123887 (11:45850434 A>T), RS1000178855 (11:45847150 G>A,C,T), RS1000229609 (11:45846783 T>A,G), RS1000243155 (11:45880539 T>C), RS1000256873 (11:45873532 C>T), RS1000328210 (11:45854512 C>G,T), RS1000353182 (11:45879644 G>A,C), RS1000481537 (11:45860703 C>G,T), RS1000592868 (11:45875078 G>A), RS1000724619 (11:45852407 T>A), RS1000764450 (11:45866857 G>A,T), RS1000784066 (11:45854263 A>G), RS1000877240 (11:45858914 A>C,G), RS1000979836 (11:45866207 C>G,T), RS1000980724 (11:45881939 T>A,C)

Disease associations

OMIM: gene MIM:603732 | disease phenotypes: MIM:214100

GenCC curated gene-disease

Mondo (1): peroxisome biogenesis disorder (MONDO:0019234)

Orphanet (1): Peroxisome biogenesis disorder (Orphanet:79189)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000568_16	Fasting blood glucose	1.000000e-14
GCST001525_28	Visceral fat	9.000000e-06
GCST001527_20	Fasting blood glucose (BMI interaction)	4.000000e-15
GCST002115_15	Axial length	2.000000e-06
GCST005186_21	Fasting blood glucose	3.000000e-13
GCST007825_1	Alzheimer’s disease or fasting glucose levels (pleiotropy)	2.000000e-13
GCST008674_12	Glycemic traits (pleiotropy)	4.000000e-10
GCST009379_316	Type 2 diabetes	4.000000e-09
GCST010244_407	Triglyceride levels	3.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0005318	axial length measurement
EFO:0004469	HOMA-B
EFO:0004530	triglyceride measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C536664	Peroxisome biogenesis disorders (supp.)
C531857	Zellweger leukodystrophy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4296116 (PROTEIN COMPLEX), CHEMBL4296247 (PROTEIN FAMILY)

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

ChEMBL bioactivities

301 potent at pChembl≥5 of 302 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.96	EC50	11	nM	CHEMBL4277833
7.70	EC50	20	nM	CHEMBL4288250
7.68	EC50	21	nM	CHEMBL4286916
7.64	EC50	23	nM	CHEMBL4286923
7.60	EC50	25	nM	CHEMBL4290598
7.55	EC50	28	nM	CHEMBL4279225
7.54	EC50	29	nM	CHEMBL3753839
7.51	EC50	31	nM	CHEMBL4289135
7.50	EC50	32	nM	CHEMBL4293352
7.48	EC50	33	nM	CHEMBL3753932
7.47	EC50	34	nM	CHEMBL4292685
7.46	EC50	35	nM	CHEMBL4277275
7.46	EC50	35	nM	CHEMBL3752819
7.46	EC50	35	nM	CHEMBL3752502
7.43	EC50	37	nM	CHEMBL4287967
7.40	EC50	40	nM	CHEMBL4288718
7.39	EC50	41	nM	CHEMBL4294270
7.38	EC50	42	nM	CHEMBL4289790
7.36	EC50	44	nM	CHEMBL4286068
7.35	EC50	45	nM	CHEMBL4283783
7.34	EC50	46	nM	CHEMBL4281214
7.30	EC50	50	nM	CHEMBL4290327
7.29	EC50	51	nM	CHEMBL4292041
7.28	EC50	53	nM	CHEMBL4290336
7.24	EC50	57	nM	CHEMBL4283668
7.23	EC50	59	nM	CHEMBL4277829
7.14	EC50	73	nM	CHEMBL4284123
7.12	EC50	76	nM	CHEMBL4287301
7.11	EC50	78	nM	CHEMBL4292482
7.10	EC50	79	nM	CHEMBL4215584
7.10	EC50	79	nM	CHEMBL4204045
7.10	EC50	80	nM	CHEMBL4278290
7.10	EC50	79	nM	CHEMBL4280285
7.09	EC50	81	nM	CHEMBL4277405
7.08	EC50	83	nM	CHEMBL4281175
7.08	EC50	84	nM	CHEMBL4285073
7.07	EC50	86	nM	CHEMBL4278653
7.05	EC50	90	nM	CHEMBL1446115
7.02	EC50	95	nM	CHEMBL4284237
7.00	EC50	100	nM	CHEMBL3752323
7.00	EC50	100	nM	CHEMBL3753078
7.00	EC50	100	nM	CHEMBL1487843
6.95	EC50	113	nM	CHEMBL4284751
6.91	EC50	123	nM	CHEMBL3752018
6.90	EC50	125	nM	CHEMBL4292764
6.90	EC50	127	nM	CHEMBL4281572
6.89	EC50	128	nM	CHEMBL4213720
6.89	EC50	128	nM	CHEMBL3753693
6.83	EC50	149	nM	CHEMBL4211895
6.83	EC50	149	nM	CHEMBL4294461

PubChem BioAssay actives

54 with measured affinity, of 55 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-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-propan-2-ylpiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.0790	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-fluoropiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.0790	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-4-methylpiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1280	uM
3-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-azabicyclo[4.1.0]heptan-4-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1490	uM
2-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-2-azabicyclo[2.2.1]heptan-3-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1630	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3,3-dimethylpyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1640	uM
3-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-azabicyclo[4.1.0]heptan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1670	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-phenyl-1,3-diazinan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1710	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-1,3-diazinan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1880	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]piperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1920	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3,3-difluoropiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1940	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-5-methylpyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1990	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-fluoropyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.2080	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-5-methylpiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.2240	uM
3-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-azabicyclo[3.1.0]hexan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.2460	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-propan-2-ylpyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.2610	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-methoxypiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.3300	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-ethylpiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.3320	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]imidazolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.3630	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-5-methoxypiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.3970	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-methylimidazolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4060	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-ethylpyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4170	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-4-methyl-1,3-diazinan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4170	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-methylpyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4240	uM
4-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]morpholin-3-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4470	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3,3-dimethylpiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4630	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-phenylpyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4870	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-ethyl-1,3-diazinan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4970	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-phenylimidazolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.5280	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-6-methylpiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.5410	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-phenylpiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.5470	uM
2-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-2-azabicyclo[4.1.0]heptan-3-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.5650	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-propan-2-ylimidazolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.6050	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-propan-2-yl-1,3-diazinan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.6200	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]pyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.6250	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-4-methylimidazolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.6670	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3,3-difluoropyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.7160	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-methyl-1,3-diazinan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.7190	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-6-methyl-1,3-diazinan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.7420	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-5-methyl-1,3-diazinan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.8330	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-methoxypyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.8550	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-(furan-2-ylmethyl)methanesulfonamide	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.8700	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-4-methylpyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	1.0330	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-ethylimidazolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	1.0590	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-5-methoxy-1,3-diazinan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	1.1210	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-4-methoxypyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	1.1380	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-methylpiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	1.1530	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-5-methylimidazolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	1.1860	uM
2-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3,4-dihydroisoquinolin-1-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	1.3610	uM
2-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3H-isoindol-1-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	1.4870	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
KL001	affects binding, decreases reaction, increases expression, decreases expression, increases stability	3
bisphenol A	increases expression, decreases methylation, affects cotreatment	2
cobaltous chloride	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation	2
Hydrogen Peroxide	affects cotreatment, affects expression, affects reaction	2
aristolochic acid I	increases expression	1
trichostatin A	affects expression	1
sodium arsenite	decreases expression	1
epigallocatechin gallate	affects cotreatment, affects expression, affects reaction	1
gallocatechol	affects cotreatment, affects expression, affects reaction	1
epicatechin gallate	affects cotreatment, affects expression, affects reaction	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
CPG-oligonucleotide	increases expression	1
abrine	increases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	increases methylation	1
Acetaminophen	increases expression	1
Atrazine	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Gallic Acid	affects reaction, affects cotreatment, affects expression	1
Indomethacin	affects cotreatment, increases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4184983	Binding	Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	Carbazole-containing amides and ureas: Discovery of cryptochrome modulators as antihyperglycemic agents. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A0T2	SEES3-1V human CRY2, clone1	Embryonic stem cell	Male
CVCL_A0T3	SEES3-1V human CRY2, clone2	Embryonic stem cell	Male
CVCL_A0T4	SEES3-1V human CRY2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01838941	PHASE3	COMPLETED	Betaine and Peroxisome Biogenesis Disorders
NCT03856866	PHASE2	COMPLETED	Hydroxychloroquine Administration for Reduction of Pexophagy
NCT01668186	Not specified	RECRUITING	Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD)
NCT03440905	Not specified	COMPLETED	Proxy-Reported Symptoms and Quality of Life Survey in Zellweger Spectrum Disorders
NCT06190626	Not specified	RECRUITING	Longitudinal Prospective Natural History Study of Retinopathy in Zellweger Spectrum Disorder