PML

Summary

PML (PML nuclear body scaffold, HGNC:9113) is a protein-coding gene on chromosome 15q24.1, encoding Protein PML (P29590). Functions via its association with PML-nuclear bodies (PML-NBs) in a wide range of important cellular processes, including tumor suppression, transcriptional regulation, apoptosis, senescence, DNA damage response, and viral defense mechanisms. In precision oncology, PML B2 DOMAIN MUTATION is associated with resistance to Tretinoin in Acute Promyelocytic Leukemia (CIViC Level B); 3 further curated variant–drug associations are listed below.

The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. This phosphoprotein localizes to nuclear bodies where it functions as a transcription factor and tumor suppressor. Its expression is cell-cycle related and it regulates the p53 response to oncogenic signals. The gene is often involved in the translocation with the retinoic acid receptor alpha gene associated with acute promyelocytic leukemia (APL). Extensive alternative splicing of this gene results in several variations of the protein’s central and C-terminal regions; all variants encode the same N-terminus. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 5371 — RefSeq curated summary.

At a glance

• GWAS associations: 23
• Clinical variants (ClinVar): 151 total
• Phenotypes (HPO): 36
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 4 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• Transcription factor: yes — 19 downstream targets (CollecTRI)
• MANE Select transcript: NM_033238

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9113
Approved symbol	PML
Name	PML nuclear body scaffold
Location	15q24.1
Locus type	gene with protein product
Status	Approved
Aliases	MYL, TRIM19, RNF71
Ensembl gene	ENSG00000140464
Ensembl biotype	protein_coding
OMIM	102578
Entrez	5371

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 19 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000268058, ENST00000268059, ENST00000354026, ENST00000359928, ENST00000395132, ENST00000395135, ENST00000435786, ENST00000436891, ENST00000562086, ENST00000563500, ENST00000564428, ENST00000564725, ENST00000565239, ENST00000565317, ENST00000565898, ENST00000566068, ENST00000567543, ENST00000567606, ENST00000569161, ENST00000569477, ENST00000569965, ENST00000570213, ENST00000868523

RefSeq mRNA: 9 — MANE Select: NM_033238 NM_002675, NM_033238, NM_033239, NM_033240, NM_033244, NM_033246, NM_033247, NM_033249, NM_033250

CCDS: CCDS10255, CCDS10256, CCDS10257, CCDS10258, CCDS45297, CCDS45298, CCDS45299, CCDS45300, CCDS58386

Canonical transcript exons

ENST00000268058 — 9 exons

Exon	Start	End
ENSE00000943227	73998004	73998476
ENSE00000943230	74032572	74032715
ENSE00001390455	74033156	74033414
ENSE00001616142	74042989	74043139
ENSE00001837919	74044221	74047827
ENSE00003589552	74022828	74023408
ENSE00003598656	74024857	74024927
ENSE00003629382	74034478	74034530
ENSE00003889653	73994716	73994941

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 94.68.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 84.0607 / max 822.2641, expressed in 1825 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147638	71.7415	1825
147639	11.6888	1759
147637	0.6304	362

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
omental fat pad	UBERON:0010414	94.68	gold quality
peritoneum	UBERON:0002358	94.64	gold quality
body of uterus	UBERON:0009853	94.08	gold quality
upper lobe of left lung	UBERON:0008952	94.07	gold quality
endocervix	UBERON:0000458	93.79	gold quality
ectocervix	UBERON:0012249	93.77	gold quality
right lung	UBERON:0002167	93.67	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.64	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.61	gold quality
right uterine tube	UBERON:0001302	93.41	gold quality
apex of heart	UBERON:0002098	93.34	gold quality
right lobe of thyroid gland	UBERON:0001119	93.05	gold quality
left lobe of thyroid gland	UBERON:0001120	93.01	gold quality
upper lobe of lung	UBERON:0008948	92.95	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.94	gold quality
left uterine tube	UBERON:0001303	92.78	gold quality
minor salivary gland	UBERON:0001830	92.70	gold quality
sural nerve	UBERON:0015488	92.70	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.64	gold quality
nerve	UBERON:0001021	92.58	gold quality
tibial nerve	UBERON:0001323	92.58	gold quality
skin of leg	UBERON:0001511	92.54	gold quality
granulocyte	CL:0000094	92.35	gold quality
mucosa of stomach	UBERON:0001199	92.30	gold quality
right coronary artery	UBERON:0001625	92.11	gold quality
thyroid gland	UBERON:0002046	92.00	gold quality
skin of abdomen	UBERON:0001416	91.86	gold quality
ascending aorta	UBERON:0001496	91.50	gold quality
spleen	UBERON:0002106	91.43	gold quality
thoracic aorta	UBERON:0001515	91.40	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.48

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

19 targets.

Target	Regulation
BAX	Activation
CASP3	Activation
CCND1	Repression
CCNT1	Unknown
CDKN1A	Activation
EAF2	Repression
EGFR	Repression
EP300	Activation
FLT3	Activation
GRIP1	Activation
HCK	Unknown
HIPK2	Activation
IFNB1	Activation
NR4A1	Repression
PML	Activation
TNFAIP3	Repression
TNFSF10	Activation
TP53	Unknown
UBA7	Repression

Upstream regulators (CollecTRI, top): ARID3A, CEBPB, CTNNB1, DNMT1, IRF3, IRF9, JUN, MYC, NFKB, NFKBIA, NKX3-1, PML, RARA, RUNX1, SP1, SSRP1, STAT1, STAT2, STAT5A, TP53

miRNA regulators (miRDB)

1 targeting PML, 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-6858-3P	96.37	64.41	771

Literature-anchored findings (GeneRIF, showing 40)

• UBE1L is a retinoid target that triggers PML/RARalpha degradation and apoptosis in acute promyelocytic leukemia (PMID:11891284)
• contributes to innate immunity, defining host susceptibility to viral infections and immunopathology (PMID:11907221)
• Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. (PMID:12006491)
• variant-type PML-RAR(alpha) fusion transcript in acute promyelocytic leukemia (PMID:12032336)
• Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions. (PMID:12032831)
• induced PML in a mouse model (PMID:12060771)
• represses A20-mediated transcription. (PMID:12080044)
• Of seven known PML isoforms, only PML IV is capable of causing premature senescence in PML +/+ murine and human primary fibroblasts but not in PML -/- murine cells, providing the first evidence for functional differences among these isoforms. (PMID:12093737)
• PML is a key stress-responsive regulator of eIF4E mRNA-dependent transport. PML inhibition of eIF4E depends on its association with the eIF4E nuclear body. (PMID:12167712)
• PML does not affect herpes simplex virus 1 replication or the changes in the localization of ICP0 through infection (PMID:12186918)
• PML is a target gene of beta-catenin and plakoglobin, and coactivates beta-catenin-mediated transcription. (PMID:12384561)
• PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2 (PMID:12402044)
• SUMO-1 protease-1 regulates gene transcription through PML (PMID:12419228)
• Purified RINGs, including PML, self-assemble into supramolecular structures in vitro that resemble those they form in cells. Self-assembly controls and amplifies reduction of 5’ mRNA cap affinity of eIF4E by PML. (PMID:12438698)
• Cryptic translocation of PML/RARA on 17q. A rare event in acute promyelocytic leukemia. (PMID:12505266)
• PML inhibited STAT3 activity in NIH3T3, 293T, HepG2, and 32D cells. PML formed a complex with STAT3 through B-box and COOH terminal regions in vitro and in vivo, thereby inhibiting its DNA binding activity. (PMID:12506013)
• In human cell lines, PML is not involved directly in the regulation of MHC class I expression. (PMID:12506025)
• PML induces apoptosis through repression of the NF-kappaB survival pathway. (PMID:12540841)
• Promyelocytic leukemia protein (PML) functions as a glucocorticoid receptor co-activator by sequestering Daxx to the PML oncogenic domains (PODs) to enhance its transactivation potential. (PMID:12595526)
• herpes simplex virus type 1 ICP4 is recruited into foci juxtaposed to ND10 (PML) in live, infected cells (PMID:12610143)
• findings strongly suggest that increased promyelocytic leukemia protein expression is associated with growth inhibition and differentiation of human neuroblastoma cells (PMID:12647219)
• role of interaction in recruiting cyclin T1 to nuclear bodies (PMID:12727882)
• PML regulates TopBP1 functions by association and stabilization of the protein in response to IR-induced DNA damage (PMID:12773567)
• PML recruits Chk2 and p53 into the PML nuclear bodies and enhances p53/Chk2 interaction (PMID:12810724)
• PML protein colocalizes and interacts with RFN36. (PMID:12837286)
• PML is required for homeodomain-interacting protein kinase 2 (HIPK2)-mediated p53 phosphorylation and cell cycle arrest but is dispensable for the formation of HIPK domains. (PMID:12907596)
• We show here that ZIPK is present in PODs, where it colocalizes with and binds to proapoptotic protein Daxx. (PMID:12917339)
• alternative splicing and role implicated in interaction with HIV-1 (PMID:14526201)
• Results suggest that adenovirus type 5 has evolved a unique strategy that leads to the sustained neutralization of promyelocytic leukaemia protein bodies throughout infection, thereby ensuring optimal viral proliferation. (PMID:14528266)
• Leukemia-associated translocation products able to activate RAS modify PML and render cells sensitive to arsenic-induced apoptosis. (PMID:14534537)
• PML-induced apoptosis by down-regulation of Survivin. (PMID:14597622)
• The ectopic expression of the acute promyelocytic leukemia-specific PML/RARalpha oncoprotein in U-937 cells results in induction of TF mRNA and promoter activity (PMID:14597990)
• DNA sequence variations resulting in a truncated PML protein was identified in acute promyelocytic leukemia cases that displayed retinoic acid resistance and a very poor prognosis (PMID:14630830)
• PML and the PML-NB act as molecular hubs for the induction and/or reinforcement of programmed cell death through a selective and dynamic regulation of proapoptotic transcriptional events. (PMID:14663483)
• Together our results suggest that PML may suppress prostate cancer cell growth by inhibiting AR transactivation and/or enhancing p53 activity. (PMID:14715247)
• Data suggest that promyelocytic leukemia (PML) bodies form in nuclear compartments of high transcriptional activity, but they do not directly regulate transcription of genes in these compartments. (PMID:14970191)
• PML protein expression is frequently lost in human cancers of various histologic origins, and its loss associates with tumor grade and progression in some tumor histotypes (PMID:14970276)
• PML is a direct p53 target that modulates p53 effector functions. (PMID:14992722)
• Results demonstrate that transcription activity associated with PML bodies is selectively repressed by the recruitment of Bach2 around PML bodies (PMID:15060166)
• acute promyelocytic leukemia cell differentiation parallels transcriptional activation through PML-RARA-RXR oligomers (PMID:15096541)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pml	ENSMUSG00000036986
rattus_norvegicus	Pml	ENSRNOG00000008400

Paralogs (80): MID2 (ENSG00000080561), TRIM9 (ENSG00000100505), MID1 (ENSG00000101871), MEFV (ENSG00000103313), TRIM35 (ENSG00000104228), TRIM14 (ENSG00000106785), TRIM37 (ENSG00000108395), TRIM2 (ENSG00000109654), TRIM3 (ENSG00000110171), TRIM38 (ENSG00000112343), TRIM62 (ENSG00000116525), TRIM67 (ENSG00000119283), TRIM32 (ENSG00000119401), BSPRY (ENSG00000119411), TRIM25 (ENSG00000121060), TRIM6 (ENSG00000121236), TRIM24 (ENSG00000122779), TRIM51 (ENSG00000124900), TRIM28 (ENSG00000130726), TRIM21 (ENSG00000132109), TRIM5 (ENSG00000132256), TRIM22 (ENSG00000132274), TRIM47 (ENSG00000132481), TRIM45 (ENSG00000134253), TRIM29 (ENSG00000137699), TRIM54 (ENSG00000138100), TRIM65 (ENSG00000141569), TRIM43B (ENSG00000144010), TRIM43 (ENSG00000144015), TRIM7 (ENSG00000146054), TRIM41 (ENSG00000146063), TRIM50 (ENSG00000146755), TRIM4 (ENSG00000146833), TRIM55 (ENSG00000147573), TRIM48 (ENSG00000150244), TRIM36 (ENSG00000152503), TRIM11 (ENSG00000154370), TRIM74 (ENSG00000155428), TRIM42 (ENSG00000155890), TRIM63 (ENSG00000158022)

Protein

Protein identifiers

Protein PML — P29590 (reviewed: P29590)

Alternative names: E3 SUMO-protein ligase PML, Promyelocytic leukemia protein, RING finger protein 71, RING-type E3 SUMO transferase PML, Tripartite motif-containing protein 19

All UniProt accessions (6): P29590, H3BRN3, H3BT29, H3BT57, H3BUJ5, H3BVD2

UniProt curated annotations — full annotation on UniProt →

Function. Functions via its association with PML-nuclear bodies (PML-NBs) in a wide range of important cellular processes, including tumor suppression, transcriptional regulation, apoptosis, senescence, DNA damage response, and viral defense mechanisms. Acts as the scaffold of PML-NBs allowing other proteins to shuttle in and out, a process which is regulated by SUMO-mediated modifications and interactions. Inhibits EIF4E-mediated mRNA nuclear export by reducing EIF4E affinity for the 5’ 7-methylguanosine (m7G) cap of target mRNAs. Isoform PML-4 has a multifaceted role in the regulation of apoptosis and growth suppression: activates RB1 and inhibits AKT1 via interactions with PP1 and PP2A phosphatases respectively, negatively affects the PI3K pathway by inhibiting MTOR and activating PTEN, and positively regulates p53/TP53 by acting at different levels (by promoting its acetylation and phosphorylation and by inhibiting its MDM2-dependent degradation). Isoform PML-4 also: acts as a transcriptional repressor of TBX2 during cellular senescence and the repression is dependent on a functional RBL2/E2F4 repressor complex, regulates double-strand break repair in gamma-irradiation-induced DNA damage responses via its interaction with WRN, acts as a negative regulator of telomerase by interacting with TERT, and regulates PER2 nuclear localization and circadian function. Isoform PML-6 inhibits specifically the activity of the tetrameric form of PKM. The nuclear isoforms (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5) in concert with SATB1 are involved in local chromatin-loop remodeling and gene expression regulation at the MHC-I locus. Isoform PML-2 is required for efficient IFN-gamma induced MHC II gene transcription via regulation of CIITA. Cytoplasmic PML is involved in the regulation of the TGF-beta signaling pathway. PML also regulates transcription activity of ELF4 and can act as an important mediator for TNF- and IFN-alpha-mediated inhibition of endothelial cell network formation and migration. Exhibits antiviral activity against both DNA and RNA viruses. The antiviral activity can involve one or several isoform(s) and can be enhanced by the permanent PML-NB-associated protein DAXX or by the recruitment of p53/TP53 within these structures. Isoform PML-4 restricts varicella zoster virus (VZV) via sequestration of virion capsids in PML-NBs thereby preventing their nuclear egress and inhibiting formation of infectious virus particles. The sumoylated isoform PML-4 restricts rabies virus by inhibiting viral mRNA and protein synthesis. The cytoplasmic isoform PML-14 can restrict herpes simplex virus-1 (HHV-1) replication by sequestering the viral E3 ubiquitin-protein ligase ICP0 in the cytoplasm. Isoform PML-6 shows restriction activity towards human cytomegalovirus (HHV-5) and influenza A virus strains PR8(H1N1) and ST364(H3N2). Sumoylated isoform PML-4 and isoform PML-12 show antiviral activity against encephalomyocarditis virus (EMCV) by promoting nuclear sequestration of viral polymerase (P3D-POL) within PML NBs. Isoform PML-3 exhibits antiviral activity against poliovirus by inducing apoptosis in infected cells through the recruitment and the activation of p53/TP53 in the PML-NBs. Isoform PML-3 represses human foamy virus (HFV) transcription by complexing the HFV transactivator, bel1/tas, preventing its binding to viral DNA. PML may positively regulate infectious hepatitis C viral (HCV) production and isoform PML-2 may enhance adenovirus transcription. Functions as an E3 SUMO-protein ligase that sumoylates (HHV-5) immediate early protein IE1, thereby participating in the antiviral response. Isoforms PML-3 and PML-6 display the highest levels of sumoylation activity.

Subunit / interactions. Key component of PML bodies. PML bodies are formed by the interaction of PML homodimers (via SUMO-binding motif) with sumoylated PML, leading to the assembly of higher oligomers. Several types of PML bodies have been observed. PML bodies can form hollow spheres that can sequester target proteins inside. Interacts (via SUMO-binding motif) with sumoylated proteins. Interacts (via C-terminus) with p53/TP53. Recruits p53/TP53 and CHEK2 into PML bodies, which promotes p53/TP53 phosphorylation at ‘Ser-20’ and prevents its proteasomal degradation. Interacts with MDM2, and sequesters MDM2 in the nucleolus, thereby preventing ubiquitination of p53/TP53. Interaction with PML-RARA oncoprotein and certain viral proteins causes disassembly of PML bodies and abolishes the normal PML function. Interacts with HIPK2, TERT, SIRT1, TOPBP1, TRIM27 and TRIM69. Interacts with ELF4 (via C-terminus). Interacts with ITPR3. Interacts (in the cytoplasm) with TGFBR1, TGFBR2 and PKM. Interacts (via the coiled-coil domain and when sumoylated) with SATB1. Interacts with UBE2I; the interaction is enhanced by arsenic binding. Interacts (PML-RARA oncoprotein, via the coiled-coil domain) with UBE2I; the interaction is enhanced by arsenic binding and is required for PML-RARA oncoprotein sumoylation and inhibition of RARA transactivational activity. Interacts with RB1, PPP1A, SMAD2, SMAD3, DAXX, RPL11 and MTOR. Interacts with PPARGC1A and KAT2A. Interacts with CSNK2A1 and CSNK2A3. Interacts with ANKRD2; the interaction is direct. Interacts (via SUMO-interacting motif) with sumoylated MORC3. Isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4, isoform PML-5 and isoform PML-6 interact with RNF4. Isoform PML-1 interacts with NLRP3. Isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5 interact with MAGEA2, RBL2, PER2 and E2F4. Isoform PML-2 interacts with CIITA. Isoform PML-2, isoform PML-3 and isoform PML-4 interact with TBX2. Isoform PML-4 interacts with RANBP2, HDAC7, KAT6A, WRN, PIN1, TBX3 and phosphorylated MAPK1/ERK2. Isoform PML-4 interacts with the CTNNB1 and TCF7L2/TCF4 complex. Isoform PML-4 preferentially interacts with MAPK7/BMK1 although other isoforms (isoform PML-1, isoform PML-2, isoform PML-3 and isoform PML-6) also interact with it. Isoform PML-12 interacts with PIAS1, PIAS2 (isoform PIAS2-alpha) and CSNK2A1/CK2. Interacts with TRIM16. Interacts with PRDM1/Blimp-1. Interacts (via RING-type zinc finger) with EIF4E; the interaction results in conformational changes of both interacting proteins and reduces EIF4E affinity for the 5’ m7G cap of mRNA, thus reducing EIF4E-mediated mRNA nuclear export. (Microbial infection) Interacts with Lassa virus Z protein and rabies virus phosphoprotein. (Microbial infection) Isoform PML-1 interacts with herpes simplex virus-1/HHV-1 ICP0. (Microbial infection) Isoform PML-2 interacts with human adenovirus 2 E1A and this interaction stimulates E1A-dependent transcriptional activation. (Microbial infection) Isoform PML-4 interacts with VZV capsid protein VP26/ORF23 capsid protein. (Microbial infection) The sumoylated isoform PML-4 interacts with encephalomyocarditis virus (EMCV) RNA-directed RNA polymerase 3D-POL (P3D-POL). (Microbial infection) Isoform PML-6 interacts with moloney murine leukemia virus (MoMLV) integrase (IN) and reverse transcriptase (RT). (Microbial infection) Isoform PML-4 and isoform PML-5 interact with human adenovirus 5 E1B-55K protein; these interactions promote efficient subnuclear targeting of E1B-55K to PML nuclear bodies. (Microbial infection) Isoform PML-3 interacts (via RING-type zinc finger) with human foamy virus bel1/tas and bet. (Microbial infection) Interacts with human cytomegalovirus (HHV-5) immediate early protein IE1; this interaction mediates PML desumoylation and PML-mediated sumoylation of IE1.

Subcellular location. Nucleus. Nucleoplasm. Cytoplasm. PML body. Nucleolus. Endoplasmic reticulum membrane. Early endosome membrane.

Post-translational modifications. Ubiquitinated; mediated by RNF4, RNF111, UHRF1, UBE3A/E6AP, BCR(KLHL20) E3 ubiquitin ligase complex E3 ligase complex, SIAH1 or SIAH2 and leading to subsequent proteasomal degradation. Ubiquitination by BCR(KLHL20) E3 ubiquitin ligase complex E3 ligase complex requires CDK1/2-mediated phosphorylation at Ser-518 which in turn is recognized by prolyl-isopeptidase PIN1 and PIN1-catalyzed isomerization further potentiates PML interaction with KLHL20. ‘Lys-6’-, ‘Lys-11’-, ‘Lys-48’- and ‘Lys-63’-linked polyubiquitination by RNF4 is polysumoylation-dependent. Ubiquitination by RNF111 is polysumoylation-dependent. Sumoylation regulates PML’s: stability in response to extracellular or intracellular stimuli, transcription directly and indirectly, through sequestration of or dissociation of the transcription factors from PML-NBs, ability to regulate apoptosis and its anti-viral activities. It is also essential for: maintaining proper PML nuclear bodies (PML-NBs) structure and normal function, recruitment of components of PML-NBs, the turnover and retention of PML in PML-NBs and the integrity of PML-NBs. Undergoes ‘Lys-11’-linked sumoylation. Sumoylation on all three sites (Lys-65, Lys-160 and Lys-490) is required for nuclear body formation. Sumoylation on Lys-160 is a prerequisite for sumoylation on Lys-65. Lys-65 and Lys-160 are sumoylated by PISA1 and PIAS2. PIAS1-mediated sumoylation of PML promotes its interaction with CSNK2A1/CK2 and phosphorylation at Ser-565 which in turn triggers its ubiquitin-mediated degradation. PIAS1-mediated sumoylation of PML-RARA promotes its ubiquitin-mediated degradation. The PML-RARA fusion protein requires the coiled-coil domain for sumoylation. Sumoylation at Lys-490 by RANBP2 is essential for the proper assembly of PML-NBs. SUMO1P1/SUMO5 conjugated PML at Lys-160, Lys-380, Lys-400, Lys-490 and Lys-497, but Lys-380, Lys-400 and Lys-497 are not key acceptor lysines. SUMO1P1/SUMO5 forms polymeric chain on Lys-160 of PML by successive conjugation at ‘Lys-18’; facilitating recruitment of PML-NB components, which enlarges PML. SUMO1P1/SUMO5 conjugation of PML increases SUMO2/3 conjugation, which leads to the recruitment of RNF4 and ubiquitin-dependent disintegration of PML-NBs. SUMO1P1/SUMO5 monoconjugated Lys-490. DNA damage triggers its sumoylation while some but not all viral infections can abolish sumoylation. Desumoylated by SENP1, SENP2, SENP3, SENP5 and SENP6. Arsenic induces PML and PML-RARA polysumoylation and their subsequent RNF4-dependent ubiquitination and proteasomal degradation, and is used as treatment in acute promyelocytic leukemia (APL). The nuclear isoforms (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4, isoform PML-5 and isoform PML-6) show an increased sumoylation in response to arsenic trioxide. The cytoplasmic isoform PML-7 is not sumoylated. Phosphorylation is a major regulatory mechanism that controls PML protein abundance and the number and size of PML nuclear bodies (PML-NBs). Phosphorylated in response to DNA damage, probably by ATR. HIPK2-mediated phosphorylation at Ser-8, Ser-36 and Ser-38 leads to increased accumulation of PML protein and its sumoylation and is required for the maximal pro-apoptotic activity of PML after DNA damage. CHEK2-mediated phosphorylation at Ser-117 is important for PML-mediated apoptosis following DNA damage. MAPK1-mediated phosphorylations at Ser-403, Ser-505, Ser-527 and Ser-530 and CDK1/2-mediated phosphorylation at Ser-518 promote PIN1-dependent PML degradation. CK2-mediated phosphorylation at Ser-565 primes PML ubiquitination via an unidentified ubiquitin ligase. (Microbial infection) Upon infection with Epstein-Barr virus, phosphorylated by CK2. Viral EBNA1 increases the association of CK2 with PML proteins, which increases PML phosphorylation by CK2, triggering the USP7-dependent polyubiquitylation and degradation of PML. Acetylation at Lys-487 is essential for its nuclear localization. Deacetylated at Lys-487 by SIRT1 and this deacetylation promotes PML control of PER2 nuclear localization. (Microbial infection) Immediate early protein IE1 of human cytomegalovirus (HHV-5) interferes with the sumoylation of PML. Immediate early protein IE1 inhibits PML de novo sumoylation. (Microbial infection) Cleaved at two different sites by enterovirus 71 protease 3C, leading to impaired PML-Nuclear bodies formation.

Disease relevance. A chromosomal aberration involving PML may be a cause of acute promyelocytic leukemia (APL). Translocation t(15;17)(q21;q21) with RARA. The PML breakpoints (type A and type B) lie on either side of an alternatively spliced exon.

Domain organisation. The coiled-coil domain mediates a strong homo/multidimerization activity essential for core assembly of PML-NBs. Interacts with PKM via its coiled-coil domain. The B box-type zinc binding domain and the coiled-coil domain mediate its interaction with PIAS1. Binds arsenic via the RING-type zinc finger. (Microbial infection) The RING-type zinc finger is necessary for the sumoylation of human cytomegalovirus (HHV-5) immediate early protein IE1. The unique C-terminal domains of isoform PML-2 and isoform PML-5 play an important role in regulating the localization, assembly dynamics, and functions of PML-NBs. The Sumo interaction motif (SIM) is required for efficient ubiquitination, recruitment of proteasome components within PML-NBs and PML degradation in response to arsenic trioxide.

Induction. By interferons alpha, beta and gamma. Up-regulated by IRF3 and p53/TP53.

Pathway. Protein modification; protein sumoylation.

Miscellaneous. Non-canonical splice sites. Might alternatively represent a polymorphic variation.

Isoforms (12)

UniProt ID	Names	Canonical?
P29590-1	PML-1, PML-I, TRIM19alpha	yes
P29590-8	PML-2, PML-II, TRIM19kappa
P29590-9	PML-3, PML-III
P29590-5	PML-4, PML-IV, PML-X, TRIM19zeta
P29590-2	PML-5, PML-2, PML-V, TRIM19beta
P29590-4	PML-6, PML-3B, PML-VI, TRIM19epsilon
P29590-10	PML-7, PML-VII, TRIM19theta
P29590-3	PML-8, PML-2G, PML-IIG, TRIM19gamma
P29590-11	PML-11, PML-1A, PML-IA
P29590-12	PML-12, PML-4A, PML-IVA, TRIM19lambda
P29590-13	PML-13, PML-2A, PML-IIA
P29590-14	PML-14, PML-6B, PML-VIB, TRIM19eta, TRIM19iota

RefSeq proteins (9): NP_002666, NP_150241, NP_150242, NP_150243, NP_150247, NP_150249, NP_150250, NP_150252, NP_150253 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000315	Znf_B-box	Domain
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR018957	Znf_C3HC4_RING-type	Domain
IPR021978	PML-like_CC	Domain
IPR047153	TRIM45/56/19-like	Family
IPR057617	PML_C	Domain

Pfam: PF00097, PF12126, PF22586, PF25244

UniProt features (139 total): mutagenesis site 24, cross-link 24, modified residue 21, binding site 16, splice variant 15, strand 9, turn 5, sequence conflict 4, site 4, region of interest 4, zinc finger region 3, compositionally biased region 3, helix 3, chain 1, coiled-coil region 1, sequence variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
6UYR	X-RAY DIFFRACTION	1.3
6UYV	X-RAY DIFFRACTION	1.4
6UYP	X-RAY DIFFRACTION	1.42
4WJO	X-RAY DIFFRACTION	1.46
4WJN	X-RAY DIFFRACTION	1.5
6UYQ	X-RAY DIFFRACTION	1.5
6UYS	X-RAY DIFFRACTION	1.59
5YUF	X-RAY DIFFRACTION	1.6
6UYO	X-RAY DIFFRACTION	1.64
6UYU	X-RAY DIFFRACTION	1.66
6UYT	X-RAY DIFFRACTION	1.66
8DJH	X-RAY DIFFRACTION	1.77
8DJI	X-RAY DIFFRACTION	1.97
6IMQ	X-RAY DIFFRACTION	2.06
8J2P	X-RAY DIFFRACTION	2.09
8J25	X-RAY DIFFRACTION	2.6
8YTC	ELECTRON MICROSCOPY	5.3
1BOR	SOLUTION NMR
2MVW	SOLUTION NMR
2MWX	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P29590-F1	71.17	0.37

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 (4): 394–395 (breakpoint for translocation to form pml-rara oncogene in type a apl); 430–431 ((microbial infection) cleavage by protease 3c of enterovirus 71); 444–445 ((microbial infection) cleavage by protease 3c of enterovirus 71); 552–553 (breakpoint for translocation to form pml-rara oncogene in type b apl)

Ligand- & substrate-binding residues (16): 57; 60; 72; 74; 77; 80; 88; 91; 129; 132; 151; 155 …

Post-translational modifications (45): 565, 518, 527, 530, 8, 36, 38, 48, 117, 403, 487, 493, 504, 505, 512, 515, 518, 527, 530, 565 …

Mutagenesis-validated functional residues (24):

Position	Phenotype
160	loss of 2 sumoylations; when associated with or without r-65. no sumoylation nor nuclear body formation; when associated
380	does not affect sumo1p1/sumo5 conjugation.
400	does not affect sumo1p1/sumo5 conjugation.
430	loss of cleavage by enterovirus 71 protease 3c.
444	loss of cleavage by enterovirus 71 protease 3c.
487	loss of nuclear localization; when associated with a-490.
487	loss of nuclear localization. reduced acetylation. further decrease in acetylation; when associated with r-515.
490	loss of nuclear localization; when associated with a-487.
490	abolished conjugation of one sumo1p1/sumo5. loss of 2 sumoylations; when associated with r-65 with or without r-133. no
490	loss of 2 sumoylations; when associated with r-65 with or without r-133. no effect on nuclear body formation; when assoc
497	does not affect sumo1p1/sumo5 conjugation.
515	slightly reduced acetylation. further decrease in acetylation; when associated with r-487.
518	abolishes ubiquitination by the bcr(klhl20) e3 ubiquitin ligase complex.
556–559	abolishes sumo1 binding.
57	strongly reduced sumoylation; when associated with s-60.
60	strongly reduced sumoylation; when associated with s-57.
65	loss of one sumoylation. no effect on nuclear body formation. loss of 2 sumoylations; when associated with r-490 with or
68	no effect on sumoylation levels.
88	no nuclear microspeckle location, no sumoylation and loss of intrinsic transcriptional repressor activity of pml-rara on
89	no nuclear microspeckle location, no sumoylation and loss of intrinsic transcriptional repressor activity of pml-rara on
133	loss of 2 sumoylations; when associated with r-65 and r-490.
150	loss of 2 sumoylations; when associated with r-65 and r-490.
160	compromised the formation of high molecular weight species of sumo1p1/sumo5 conjugation on pml. loss of 2 sumoylations;

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins
R-HSA-3232142	SUMOylation of ubiquitinylation proteins
R-HSA-6804758	Regulation of TP53 Activity through Acetylation
R-HSA-877300	Interferon gamma signaling
R-HSA-8934593	Regulation of RUNX1 Expression and Activity
R-HSA-8948747	Regulation of PTEN localization
R-HSA-9609690	HCMV Early Events
R-HSA-9616222	Transcriptional regulation of granulopoiesis
R-HSA-9920588	Dengue virus activates/modulates innate and adaptive immune responses

MSigDB gene sets: 785 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CIRCADIAN_RHYTHM, MORF_RAGE, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_YELLOW_DN, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, GOBP_MAMMARY_GLAND_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_GLAND_MORPHOGENESIS

GO Biological Process (72): response to hypoxia (GO:0001666), positive regulation of defense response to virus by host (GO:0002230), chromatin remodeling (GO:0006338), regulation of DNA-templated transcription (GO:0006355), protein targeting (GO:0006605), protein import into nucleus (GO:0006606), apoptotic process (GO:0006915), transforming growth factor beta receptor signaling pathway (GO:0007179), negative regulation of cell population proliferation (GO:0008285), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), intrinsic apoptotic signaling pathway in response to oxidative stress (GO:0008631), response to UV (GO:0009411), response to gamma radiation (GO:0010332), regulation of calcium ion transport into cytosol (GO:0010522), fibroblast migration (GO:0010761), negative regulation of angiogenesis (GO:0016525), protein sumoylation (GO:0016925), myeloid cell differentiation (GO:0030099), regulation of cell adhesion (GO:0030155), negative regulation of cell growth (GO:0030308), DNA damage response, signal transduction by p53 class mediator (GO:0030330), PML body organization (GO:0030578), protein-containing complex localization (GO:0031503), positive regulation of telomere maintenance (GO:0032206), negative regulation of telomere maintenance via telomerase (GO:0032211), endoplasmic reticulum calcium ion homeostasis (GO:0032469), negative regulation of interleukin-1 beta production (GO:0032691), circadian regulation of gene expression (GO:0032922), negative regulation of translation in response to oxidative stress (GO:0032938), response to cytokine (GO:0034097), regulation of circadian rhythm (GO:0042752), intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:0042771), entrainment of circadian clock by photoperiod (GO:0043153), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), suppression of viral release by host (GO:0044790), innate immune response (GO:0045087), cell fate commitment (GO:0045165), negative regulation of DNA-templated transcription (GO:0045892), negative regulation of mitotic cell cycle (GO:0045930), positive regulation of fibroblast proliferation (GO:0048146)

GO Molecular Function (16): DNA binding (GO:0003677), transcription coactivator activity (GO:0003713), zinc ion binding (GO:0008270), SUMO transferase activity (GO:0019789), ubiquitin protein ligase binding (GO:0031625), SUMO binding (GO:0032183), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), SMAD binding (GO:0046332), protein heterodimerization activity (GO:0046982), cobalt ion binding (GO:0050897), molecular adaptor activity (GO:0060090), ubiquitin-like protein ligase activity (GO:0061659), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (14): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), nuclear matrix (GO:0016363), PML body (GO:0016605), early endosome membrane (GO:0031901), nuclear membrane (GO:0031965), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	2
Regulation of TP53 Activity	1
Interferon Signaling	1
Transcriptional regulation by RUNX1	1
PTEN Regulation	1
HCMV Infection	1
Developmental Biology	1
Dengue Virus-Host Interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
nuclear lumen	3
negative regulation of cellular process	2
intrinsic apoptotic signaling pathway	2
transition metal ion binding	2
ubiquitin-like protein transferase activity	2
protein binding	2
protein dimerization activity	2
binding	2
intracellular membrane-bounded organelle	2
organelle membrane	2
cytoplasm	2
endomembrane system	2
response to stress	1
response to decreased oxygen levels	1
regulation of defense response to virus by host	1
chromatin organization	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
establishment of protein localization	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
cell population proliferation	1
regulation of cell population proliferation	1
DNA damage response	1
response to light stimulus	1
response to ionizing radiation	1
regulation of cellular localization	1
calcium ion transport into cytosol	1
regulation of biological quality	1
regulation of calcium ion transmembrane transport	1
ameboidal-type cell migration	1

Protein interactions and networks

STRING

2014 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PML	DAXX	Q9UER7	975
PML	SP100	P23497	918
PML	RARA	P10276	904
PML	TMBIM4	Q9HC24	898
PML	SUMO1	P55856	874
PML	TERF1	P54274	836
PML	TRIM17	Q9Y577	741
PML	SUMO2	P55855	720
PML	TRAT1	Q6PIZ9	698
PML	UBE2I	P50550	697
PML	FOXO1	Q12778	697
PML	SIRT1	Q96EB6	696
PML	TRIM27	P14373	696
PML	HIPK1	Q86Z02	674
PML	ITPR3	Q14573	670

IntAct

236 interactions, top by confidence:

A	B	Type	Score
S100B	S100A4	psi-mi:“MI:0914”(association)	0.870
SUMO1	PML	psi-mi:“MI:0407”(direct interaction)	0.830
SUMO1	PML	psi-mi:“MI:0915”(physical association)	0.830
PML	SUMO1	psi-mi:“MI:0915”(physical association)	0.830
PML	KLHL20	psi-mi:“MI:0915”(physical association)	0.810
PML	KLHL20	psi-mi:“MI:0403”(colocalization)	0.810
KLHL20	PML	psi-mi:“MI:0407”(direct interaction)	0.810
KLHL20	PML	psi-mi:“MI:0914”(association)	0.810
KLHL20	PML	psi-mi:“MI:0915”(physical association)	0.810
LDHB	LDHA	psi-mi:“MI:0914”(association)	0.800
DAXX	PML	psi-mi:“MI:0403”(colocalization)	0.790
DAXX	PML	psi-mi:“MI:0914”(association)	0.790
DAXX	PML	psi-mi:“MI:0915”(physical association)	0.790
PML	DAXX	psi-mi:“MI:0915”(physical association)	0.790
TP53	PML	psi-mi:“MI:0915”(physical association)	0.700
PML	TP53	psi-mi:“MI:0403”(colocalization)	0.700
PML	TP53	psi-mi:“MI:2364”(proximity)	0.700
PML	TP53	psi-mi:“MI:0915”(physical association)	0.700
	PML	psi-mi:“MI:0915”(physical association)	0.620
PML		psi-mi:“MI:0403”(colocalization)	0.620
PML		psi-mi:“MI:0915”(physical association)	0.620
EIF4E	PML	psi-mi:“MI:0407”(direct interaction)	0.620
PML	EIF4E	psi-mi:“MI:0407”(direct interaction)	0.620
PML	EIF4E	psi-mi:“MI:0403”(colocalization)	0.620

BioGRID (1454): TP53 (Affinity Capture-Western), PML (Affinity Capture-Western), PML (Affinity Capture-Western), PML (Affinity Capture-Western), PML (Affinity Capture-Western), RBL2 (Affinity Capture-Western), E2F4 (Affinity Capture-Western), PML (Affinity Capture-Western), PML (Affinity Capture-Western), PML (Co-localization), TBX3 (Affinity Capture-Western), PML (Affinity Capture-Western), PML (Affinity Capture-MS), PYCARD (Affinity Capture-Western), KAT6A (Far Western)

ESM2 similar proteins: A0A0G2JXN2, A2AWP8, O88842, O95267, P29590, P52734, P98174, Q1LY10, Q29RM4, Q2TBA3, Q3TAA7, Q3U0J8, Q3UTZ3, Q496Y0, Q4VX76, Q568M3, Q58D15, Q5BIM1, Q5JSP0, Q5R5M3, Q5R5T1, Q5REJ9, Q5W0U4, Q68FF6, Q69Z89, Q69ZK0, Q6PFY8, Q7TNM2, Q7Z4K8, Q7Z5H3, Q7Z6J4, Q80V85, Q8BY35, Q8BZ52, Q8C190, Q8N1F8, Q8TCU6, Q8WVR3, Q96JH8, Q99N48

Diamond homologs: A0A7I2V3R4, A4IF63, A5D7F8, A5D8S5, D2GXS7, D3ZQG6, F7H9X2, O70277, O75382, P21333, P29590, Q03601, Q28E95, Q5RBR0, Q69ZI1, Q6FPI4, Q6NRD3, Q71F54, Q7Z6J0, Q8BFW4, Q8BTM8, Q8C120, Q8IWR1, Q8NG06, Q8TEJ3, Q922Y2, Q9C040, Q9ESN6, Q9R1R2, A5WW08, Q5RF77, Q75EN0, Q80X90, Q810L3, Q96EP1, Q60953, Q61510

SIGNOR signaling

35 interactions.

A	Effect	B	Mechanism
MAPK1	up-regulates	PML	phosphorylation
MAPK3	up-regulates	PML	phosphorylation
PML	up-regulates	Apoptosis
PML	up-regulates	SMAD2	binding
PML	“up-regulates activity”	SMAD2	binding
PML	up-regulates	SMAD3	binding
PML	up-regulates	ZFYVE9	binding
CSNK2A1	down-regulates	PML	phosphorylation
MAPK7	down-regulates	PML	phosphorylation
CDK1	down-regulates	PML	phosphorylation
HIPK2	up-regulates	PML	phosphorylation
PML	“form complex”	KAT6A/PML	binding
PML	“up-regulates activity”	SMAD3	binding
PML	up-regulates	Cell_death
Gbeta	up-regulates	PML	phosphorylation
ERK1/2	up-regulates	PML	phosphorylation
Ub:E2	“up-regulates activity”	PML	ubiquitination
RNF111	“down-regulates quantity by destabilization”	PML	polyubiquitination
RNF4	“down-regulates quantity by destabilization”	PML	polyubiquitination
MAPK7	“down-regulates activity”	PML	phosphorylation
CHEK2	unknown	PML	phosphorylation
SUMO1	up-regulates	PML	sumoylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 166 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
SUMOylation of transcription factors	7	33.3×	7e-07
SUMOylation of intracellular receptors	5	14.0×	2e-03
Regulation of TP53 Degradation	5	12.2×	3e-03
SUMO E3 ligases SUMOylate target proteins	8	11.9×	7e-05
SUMOylation	8	10.9×	1e-04
Oncogenic MAPK signaling	5	10.3×	5e-03
SUMOylation of transcription cofactors	5	10.1×	5e-03
SUMOylation of DNA damage response and repair proteins	7	8.5×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein sumoylation	7	15.5×	1e-04
substantia nigra development	6	15.1×	4e-04
protein destabilization	7	13.9×	1e-04
cellular response to hydrogen peroxide	8	12.8×	8e-05
protein localization to nucleus	5	12.0×	4e-03
cellular response to heat	5	11.8×	4e-03
positive regulation of transcription initiation by RNA polymerase II	6	11.2×	2e-03
cellular senescence	5	10.1×	7e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

The PML-RARA fusion is the result of a recurrent, balanced translocation between chromosomes 15 and 17, denoted as t(15;17)(q22;q12), and a diagnostic event in acute promyelocytic leukemia (APL). Both in vitro and in vivo studies have shown sensitivity to ATRA (all-trans retinoic acid) in APL patients harboring the PML-RARA fusion. Recent interest has been shown in combining ATRA and arsenic trioxide for treating these patients, and early results seem promising. However, newly discovered mutations in the B2 domain of PML have started to show conferred resistance to ATRA in these patients.

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — LUNG.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	105
Likely benign	18
Benign	11

Top pathogenic / likely-pathogenic (0)

SpliceAI

1566 predictions. Top by Δscore:

Variant	Effect	Δscore
15:73994938:AGAG:A	donor_loss	1.0000
15:73994939:GAG:G	donor_gain	1.0000
15:73994940:AG:A	donor_loss	1.0000
15:73994941:GG:G	donor_loss	1.0000
15:73998000:CCA:C	acceptor_loss	1.0000
15:73998001:CA:C	acceptor_loss	1.0000
15:73998002:A:AG	acceptor_gain	1.0000
15:73998002:A:T	acceptor_loss	1.0000
15:73998002:AGC:A	acceptor_gain	1.0000
15:73998003:G:GG	acceptor_gain	1.0000
15:73998003:GC:G	acceptor_gain	1.0000
15:73998003:GCG:G	acceptor_gain	1.0000
15:73998003:GCGA:G	acceptor_gain	1.0000
15:73998472:ACCAG:A	donor_gain	1.0000
15:73998476:GGTG:G	donor_loss	1.0000
15:73998477:G:GA	donor_loss	1.0000
15:73998477:G:GG	donor_gain	1.0000
15:74023405:AAAG:A	donor_loss	1.0000
15:74023410:T:A	donor_loss	1.0000
15:74032570:A:AG	acceptor_gain	1.0000
15:74032571:G:GG	acceptor_gain	1.0000
15:74032571:GCCC:G	acceptor_gain	1.0000
15:74032713:GAGGT:G	donor_loss	1.0000
15:74032714:AGGTA:A	donor_loss	1.0000
15:74032716:G:A	donor_loss	1.0000
15:74032717:T:G	donor_loss	1.0000
15:74033155:GGAT:G	acceptor_gain	1.0000
15:74033358:G:GT	donor_gain	1.0000
15:74034477:GA:G	acceptor_gain	1.0000
15:74034527:CTCGG:C	donor_loss	1.0000

AlphaMissense

5750 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:73998292:T:C	C140R	0.997
15:73998439:T:C	C189R	0.997
15:74022859:T:C	C212R	0.997
15:73998259:T:C	C129R	0.995
15:73998294:C:G	C140W	0.995
15:73998325:T:C	C151R	0.995
15:73998346:T:C	F158L	0.995
15:73998348:C:A	F158L	0.995
15:73998348:C:G	F158L	0.995
15:73998440:G:A	C189Y	0.994
15:73998441:C:G	C189W	0.994
15:74022861:C:G	C212W	0.994
15:74022868:T:C	C215R	0.994
15:73998192:C:A	N106K	0.993
15:73998192:C:G	N106K	0.993
15:73998337:C:G	H155D	0.993
15:73998439:T:A	C189S	0.993
15:73998440:G:C	C189S	0.993
15:74022832:T:G	Y203D	0.993
15:74022835:T:C	C204R	0.993
15:73998043:T:C	C57R	0.992
15:73998088:T:C	C72R	0.992
15:73998261:C:G	C129W	0.992
15:73998327:C:G	C151W	0.992
15:73998103:T:C	C77R	0.991
15:73998301:T:C	C143R	0.991
15:73998316:T:C	C148R	0.991
15:73998404:T:C	F177S	0.991
15:74022837:C:G	C204W	0.991
15:74022859:T:A	C212S	0.991

dbSNP variants (sampled 300 via entrez): RS1000032580 (15:74024698 C>T), RS1000125820 (15:74018578 G>A), RS1000142814 (15:74036178 C>G), RS1000191032 (15:74017648 A>G), RS1000195067 (15:74022185 G>A), RS1000218715 (15:73997197 CA>C), RS1000224778 (15:74021987 T>C), RS1000428064 (15:74015064 A>G), RS1000500043 (15:73995711 T>A), RS1000516691 (15:74029042 T>G), RS1000524646 (15:74023911 G>C), RS1000551957 (15:74041489 C>T), RS1000555582 (15:74023467 C>A,T), RS1000569209 (15:73997545 TG>T), RS1000684510 (15:74009398 C>A)

Disease associations

OMIM: gene MIM:102578 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): breast ductal adenocarcinoma (MONDO:0005590)

Orphanet (0):

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000212	Gingival overgrowth
HP:0000225	Gingival bleeding
HP:0000421	Epistaxis
HP:0000790	Hematuria
HP:0000967	Petechiae
HP:0000978	Bruising susceptibility
HP:0000979	Purpura
HP:0001324	Muscle weakness
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001882	Decreased total leukocyte count
HP:0001892	Abnormal bleeding
HP:0001903	Anemia
HP:0001945	Fever
HP:0001974	Increased total leukocyte count
HP:0002027	Abdominal pain
HP:0002039	Anorexia
HP:0002321	Vertigo
HP:0002653	Bone pain
HP:0002716	Lymphadenopathy
HP:0002875	Exertional dyspnea
HP:0005521	Disseminated intravascular coagulation
HP:0010280	Stomatitis
HP:0011900	Hypofibrinogenemia
HP:0012378	Fatigue
HP:0025420	Diffuse alveolar hemorrhage
HP:0030140	Oral cavity bleeding
HP:0030955	Addictive alcohol use

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST000817_2	Height	4.000000e-12
GCST000817_89	Height	1.000000e-15
GCST001086_2	Paget’s disease	2.000000e-14
GCST001712_54	Myopia (pathological)	5.000000e-08
GCST002647_111	Height	2.000000e-29
GCST006079_1	Accelerometer-based physical activity measurement (fraction of time with accelerations >425 milli-gravities)	1.000000e-09
GCST006912_7	Physical activity (overall physical activity time)	1.000000e-06
GCST007387_18	Insomnia symptoms (never/rarely vs. sometimes/usually)	9.000000e-11
GCST007388_8	Insomnia symptoms (never/rarely vs. usually)	3.000000e-12
GCST008163_444	Height	4.000000e-06
GCST008362_56	Birth weight	9.000000e-09
GCST012227_298	Hip circumference adjusted for BMI	1.000000e-08
GCST012227_301	Hip circumference adjusted for BMI	5.000000e-12
GCST012227_302	Hip circumference adjusted for BMI	6.000000e-11
GCST012227_303	Hip circumference adjusted for BMI	1.000000e-15
GCST012227_304	Hip circumference adjusted for BMI	3.000000e-09
GCST012227_512	Hip circumference adjusted for BMI	4.000000e-12
GCST90000025_223	Appendicular lean mass	9.000000e-39
GCST90000026_22	Appendicular lean mass	2.000000e-18
GCST90000027_23	Appendicular lean mass	3.000000e-23
GCST90002407_594	White blood cell count	2.000000e-09
GCST90020028_1746	Hip circumference adjusted for BMI	3.000000e-09
GCST90020028_1747	Hip circumference adjusted for BMI	6.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004207	pathological myopia
EFO:0008002	physical activity measurement
EFO:0007876	insomnia measurement
EFO:0004344	birth weight
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL5465238 (CHIMERIC PROTEIN), CHEMBL6067625 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (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
CHEMBL1232461	MOLIBRESIB	2	1,538

Clinical evidence (CIViC)

Drug × variant × indication: 4 predictive associations from 4 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
PML B2 DOMAIN MUTATION	Tretinoin	Acute Promyelocytic Leukemia	Resistance	CIViC B	EID1092
PML::RARA Fusion AND PML A216V	Arsenic Trioxide	Acute Promyelocytic Leukemia	Resistance	CIViC B	EID8177
PML::RARA Fusion AND PML A216V	Tretinoin	Acute Promyelocytic Leukemia	Resistance	CIViC C	EID1093
PML::RARA Fusion AND PML L218P	Tretinoin	Acute Promyelocytic Leukemia	Resistance	CIViC C	EID1094

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.96	IC50	1090	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 35 total; 1 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178839: Inhibition of PML-RAR (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	1.0900	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	increases reaction, increases ubiquitination, affects cotreatment, increases expression, increases degradation (+14 more)	40
Tretinoin	increases degradation, increases cleavage, affects binding, decreases reaction, increases expression (+8 more)	14
sodium arsenite	increases degradation, increases sumoylation, increases ubiquitination, decreases response to substance, affects binding (+6 more)	7
Resveratrol	increases reaction, affects cotreatment, decreases expression, increases expression, affects binding (+1 more)	3
Arsenic	affects binding, increases reaction, increases degradation, decreases expression, increases abundance (+5 more)	3
Benzo(a)pyrene	increases methylation, increases mutagenesis, increases expression	3
TAK-243	affects binding, decreases reaction, increases reaction, decreases sumoylation	2
bisphenol A	affects cotreatment, decreases methylation, decreases expression	2
arsenite	affects binding, increases sumoylation, increases response to substance	2
monomethylarsonous acid	increases sumoylation, increases ubiquitination, affects cotreatment, increases degradation	2
tetraarsenic tetrasulfide	affects binding, increases degradation, increases reaction, decreases reaction, increases expression	2
(+)-JQ1 compound	decreases expression	2
Vorinostat	affects cotreatment, decreases expression, affects binding, increases reaction	2
Air Pollutants	increases oxidation, decreases expression, affects cotreatment, increases abundance	2
Vehicle Emissions	increases abundance, increases expression, decreases expression	2
Cycloheximide	decreases reaction, increases degradation, decreases degradation	2
Lipopolysaccharides	increases expression, affects response to substance	2
Nickel	increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Valproic Acid	decreases expression, increases expression	2
Zinc	increases expression, affects binding, decreases reaction	2
Cadmium Chloride	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression, increases expression	1
CB-5083	increases degradation, increases reaction, affects binding, increases ubiquitination, decreases reaction	1
FR900359	affects phosphorylation	1
ML-792	affects binding, decreases reaction, increases reaction	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1

ChEMBL screening assays

34 unique, capped per target: 34 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5378953	Binding	Induction of Flag-tagged PML/RARalpha (unknown origin) degradation overexpressed in HEK293T cells at 13 to 65 uM incubated for 16 hrs by Western blot analysis	AcGlcAs: A Novel P53-Targeting Arsenical with Potent Cellular Uptake and Cancer Cell Selectivity. — J Med Chem

Cellosaurus cell lines

36 cell lines: 33 cancer cell line, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_0005	NB4	Cancer cell line	Female
CVCL_0567	UF-1	Cancer cell line	Female
CVCL_1807	AP-1060	Cancer cell line	Male
CVCL_8811	NB4-LR1	Cancer cell line	Female
CVCL_A5K7	SEES3-1V human PML, clone1	Embryonic stem cell	Male
CVCL_A5K8	SEES3-1V human PML, clone2	Embryonic stem cell	Male
CVCL_A5K9	SEES3-1V human PML, clone3	Embryonic stem cell	Male
CVCL_B2B8	Abcam HeLa PML KO	Cancer cell line	Female
CVCL_B8MP	Abcam HCT 116 PML KO	Cancer cell line	Male
CVCL_B9AD	Abcam MCF-7 PML KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery