PML (PML nuclear body scaffold)

Gene

• Entrez ID: 5371
• Gene name: PML nuclear body scaffold
• Gene symbol: PML
• Synonyms: MYL, PP8675, RNF71, TRIM19
• Chromosome: 15
• Chromosome location: 15q24.1
• Summary: 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. [provided by RefSeq, Jul 2008]

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT018318	hsa-miR-335-5p	Microarray	18185580
MIRT042535	hsa-miR-423-3p	CLASH	23622248
MIRT043919	hsa-miR-378a-3p	CLASH	23622248

Transcription factors

Transcription factor	Regulation	Reference
ARID3A	Activation	22010578
IRF9	Activation	8681971
PML	Activation	15529177
STAT1	Activation	21115099;22589541
STAT1	Unknown	15519999
STAT2	Unknown	17062732
TP53	Activation	14992722

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000781	Component	Chromosome, telomeric region	IDA	26119943
GO:0000785	Component	Chromatin	IBA	21873635
GO:0000792	Component	Heterochromatin	IEA
GO:0001666	Process	Response to hypoxia	IDA	16915281
GO:0001932	Process	Regulation of protein phosphorylation	ISS
GO:0003677	Function	DNA binding	IEA
GO:0004842	Function	Ubiquitin-protein transferase activity	IBA	21873635
GO:0005515	Function	Protein binding	IPI	9294197, 10669754, 10684855, 11259576, 11948183, 12006491, 12529400, 12915590, 14517282, 14976184, 15195100, 15467728, 15626733, 16322229, 16873060, 16915281, 17036045, 18298799, 18511908, 20389280, 20625391, 20639899, 20832753, 21057547, 21803845, 21840486, 21988832, 21994459, 2200
GO:0005634	Component	Nucleus	IDA	9412458, 22274616
GO:0005654	Component	Nucleoplasm	IBA	21873635
GO:0005654	Component	Nucleoplasm	IDA	12915590
GO:0005654	Component	Nucleoplasm	TAS
GO:0005730	Component	Nucleolus	IDA	15195100
GO:0005737	Component	Cytoplasm	IDA	18298799
GO:0005829	Component	Cytosol	ISS
GO:0005829	Component	Cytosol	TAS
GO:0006355	Process	Regulation of transcription, DNA-templated	IMP	23007646
GO:0006606	Process	Protein import into nucleus	IEA
GO:0006919	Process	Activation of cysteine-type endopeptidase activity involved in apoptotic process	IEA
GO:0006977	Process	DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest	ISS
GO:0007050	Process	Cell cycle arrest	IBA	21873635
GO:0007179	Process	Transforming growth factor beta receptor signaling pathway	IEA
GO:0007182	Process	Common-partner SMAD protein phosphorylation	IEA
GO:0008270	Function	Zinc ion binding	IEA
GO:0008285	Process	Negative regulation of cell population proliferation	IMP	12006491
GO:0008630	Process	Intrinsic apoptotic signaling pathway in response to DNA damage	IBA	21873635
GO:0008631	Process	Intrinsic apoptotic signaling pathway in response to oxidative stress	IEA
GO:0009411	Process	Response to UV	IEA
GO:0010332	Process	Response to gamma radiation	IEA
GO:0010522	Process	Regulation of calcium ion transport into cytosol	ISS
GO:0010761	Process	Fibroblast migration	IEA
GO:0016032	Process	Viral process	IEA
GO:0016363	Component	Nuclear matrix	IEA
GO:0016525	Process	Negative regulation of angiogenesis	IMP	16915281
GO:0016567	Process	Protein ubiquitination	IEA
GO:0016605	Component	PML body	IBA	21873635
GO:0016605	Component	PML body	IDA	9412458, 9448006, 11331580, 12917339, 15195100, 17081985, 22155184, 22869143, 23007646, 23431171
GO:0016605	Component	PML body	IDA	10910364
GO:0016605	Component	PML body	TAS	9230084
GO:0030099	Process	Myeloid cell differentiation	IEA
GO:0030155	Process	Regulation of cell adhesion	IEA
GO:0030308	Process	Negative regulation of cell growth	IDA	9448006
GO:0030578	Process	PML body organization	IBA	21873635
GO:0030578	Process	PML body organization	IMP	17081985
GO:0031625	Function	Ubiquitin protein ligase binding	IPI	12915590
GO:0031901	Component	Early endosome membrane	IEA
GO:0032183	Function	SUMO binding	IPI	17081985
GO:0032206	Process	Positive regulation of telomere maintenance	IMP	26119943
GO:0032469	Process	Endoplasmic reticulum calcium ion homeostasis	ISS
GO:0032691	Process	Negative regulation of interleukin-1 beta production	IEA
GO:0032922	Process	Circadian regulation of gene expression	ISS
GO:0034097	Process	Response to cytokine	IDA	9412458
GO:0042406	Component	Extrinsic component of endoplasmic reticulum membrane	ISS
GO:0042752	Process	Regulation of circadian rhythm	ISS
GO:0042771	Process	Intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	ISS
GO:0042803	Function	Protein homodimerization activity	IPI	9230084
GO:0043153	Process	Entrainment of circadian clock by photoperiod	ISS
GO:0043161	Process	Proteasome-mediated ubiquitin-dependent protein catabolic process	IDA	22406621
GO:0045087	Process	Innate immune response	IDA	18248090
GO:0045165	Process	Cell fate commitment	IEA
GO:0045892	Process	Negative regulation of transcription, DNA-templated	IDA	9448006
GO:0045893	Process	Positive regulation of transcription, DNA-templated	IBA	21873635
GO:0046332	Function	SMAD binding	IEA
GO:0048146	Process	Positive regulation of fibroblast proliferation	IEA
GO:0048384	Process	Retinoic acid receptor signaling pathway	IEA
GO:0051457	Process	Maintenance of protein location in nucleus	IDA	17332504
GO:0051607	Process	Defense response to virus	IEA
GO:0060333	Process	Interferon-gamma-mediated signaling pathway	TAS
GO:0060444	Process	Branching involved in mammary gland duct morphogenesis	IEA
GO:0065003	Process	Protein-containing complex assembly	IDA	12915590
GO:0070059	Process	Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	IEA
GO:0071353	Process	Cellular response to interleukin-4	IEA
GO:0090398	Process	Cellular senescence	IDA	22002537, 22117195, 23431171
GO:0097191	Process	Extrinsic apoptotic signaling pathway	IEA
GO:0140037	Function	Sumo-dependent protein binding	IPI	17081986
GO:1901796	Process	Regulation of signal transduction by p53 class mediator	TAS
GO:1902187	Process	Negative regulation of viral release from host cell	IDA	18248090
GO:1990830	Process	Cellular response to leukemia inhibitory factor	IEA
GO:2000059	Process	Negative regulation of ubiquitin-dependent protein catabolic process	IMP	15195100
GO:2000779	Process	Regulation of double-strand break repair	IMP	21639834
GO:2001238	Process	Positive regulation of extrinsic apoptotic signaling pathway	IMP	21803845

Other IDs

• MIM: 102578
• HGNC: 9113
• e!Ensembl: ENSG00000140464

Protein

• UniProt ID: P29590
• Protein name: Protein PML (E3 SUMO-protein ligase PML) (EC 2.3.2.-) (Promyelocytic leukemia protein) (RING finger protein 71) (RING-type E3 SUMO transferase PML) (Tripartite motif-containing protein 19) (TRIM19)
• Protein 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. 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-alpha- 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 (PubMed:20972456, PubMed:28250117). Isoforms PML-3 and PML-6 display the highest levels of sumoylation activity (PubMed:20972456, PubMed:28250117).
• PDB: 1BOR, 2MVW, 2MWX, 4WJN, 4WJO, 5YUF, 6IMQ, 6UYO, 6UYP, 6UYQ, 6UYR, 6UYS, 6UYT, 6UYU, 6UYV
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00643	zf-B_box	124 → 166	B-box zinc finger	Domain
  PF12126	DUF3583	240 → 570	Protein of unknown function (DUF3583)	Family

• Sequence:

  MEPAPARSPRPQQDPARPQEPTMPPPETPSEGRQPSPSPSPTERAPASEEEFQFLRCQQC
  QAEAKCPKLLPCLHTLCSGCLEASGMQCPICQAPWPLGADTPALDNVFFESLQRRLSVYR
  QIVDAQAVCTRCKESADFWCFECEQLLCAKCFEAHQWFLKHEARPLAELRNQSVREFLDG
  TRKTNNIFCSNPNHRTPTLTSIYCRGCSKPLCCSCALLDSSHSELKCDISAEIQQRQEEL
  DAMTQALQEQDSAFGAVHAQMHAAVGQLGRARAETEELIRERVRQVVAHVRAQERELLEA
  VDARYQRDYEEMASRLGRLDAVLQRIRTGSALVQRMKCYASDQEVLDMHGFLRQALCRLR
  QEEPQSLQAAVRTDGFDEFKVRLQDLSSCITQGKDAAVSKKASPEAASTPRDPIDVDLPE
  EAERVKAQVQALGLAEAQPMAVVQSVPGAHPVPVYAFSIKGPSYGEDVSNTTTAQKRKCS
  QTQCPRKVIKMESEEGKEARLARSSPEQPRPSTSKAVSPPHLDGPPSPRSPVIGSEVFLP
  NSNHVASGAGEAEERVVVISSSEDSDAENSSSRELDDSSSESSDLQLEGPSTLRVLDENL
  ADPQAEDRPLVFFDLKIDNETQKISQLAAVNRESKFRVVIQPEAFFSIYSKAVSLEVGLQ
  HFLSFLSSMRRPILACYKLWGPGLPNFFRALEDINRLWEFQEAISGFLAALPLIRERVPG
  ASSFKLKNLAQTYLARNMSERSAMAAVLAMRDLCRLLEVSPGPQLAQHVYPFSSLQCFAS
  LQPLVQAAVLPRAEARLLALHNVSFMELLSAHRRDRQGGLKKYSRYLSLQTTTLPPAQPA
  FNLQALGTYFEGLLEGPALARAEGVSTPLAGRGLAERASQQS

• Sequence length: 882