Affinage

PML

Protein PML · UniProt P29590

Length
882 aa
Mass
97.6 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PML is the essential scaffold of PML nuclear bodies (PML-NBs), membraneless nuclear compartments whose biogenesis requires sequential RING-domain tetramerization and B1-box oligomerization that recruit the SUMO E2 conjugase UBC9, enabling SUMO modification of PML itself and recruited partner proteins (PMID:29599493, PMID:31439836, PMID:29535160). Within PML-NBs, PML orchestrates tumor-suppressive programs by forming a trimeric complex with p53 and CBP to drive p53 acetylation and transcriptional activation, recruiting Rb and E2F to silence proliferative genes and enforce senescence, stabilizing HIPK2/p300 against SCF(Fbx3)-mediated degradation, sequestering MDM2 to protect p53, and inhibiting mTOR–Rheb association to repress HIF-1α translation and angiogenesis (PMID:10910364, PMID:21205865, PMID:18809579, PMID:16915281). PML protein levels are regulated by CK2 phosphorylation at Ser517 that primes ubiquitin/proteasome-mediated degradation, PIAS1-dependent sumoylation that facilitates CK2 access, and RNF4 SUMO-targeted ubiquitin ligase activity, while the CRL4(WDR4) E3 ligase provides an additional degradation pathway active in lung cancer (PMID:18566754, PMID:22406621, PMID:24190887, PMID:28691927). PML-NBs additionally serve as platforms for antiviral innate immunity through interferon-induced global SUMOylation, intrinsic defense against herpes simplex virus, and DNA damage repair via recruitment of Rad51 and BRCA1 to double-strand break foci (PMID:29535160, PMID:21172801, PMID:21998700).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1998 High

    Establishing PML as a direct interactor and functional modulator of Rb addressed how PML-NBs interface with cell cycle control, showing PML preferentially binds hypophosphorylated Rb and modulates Rb-dependent transcription.

    Evidence Co-IP, deletion mutagenesis, and transcriptional reporter assays in mammalian cells

    PMID:9448006

    Open questions at the time
    • Whether PML–Rb interaction is direct or bridged by SUMO was not tested
    • In vivo relevance to senescence not yet shown
  2. 1999 Medium

    Discovery that PML sumoylation cycles with the cell cycle—conjugated in interphase, deconjugated in mitosis—revealed that post-translational modification dynamically regulates NB composition.

    Evidence Biochemical fractionation, immunofluorescence, and phosphatase inhibitor treatment in synchronized cells

    PMID:10574707

    Open questions at the time
    • The kinase(s) responsible for mitotic PML phosphorylation were not identified
    • Functional consequence of mitotic desumoylation for daughter-cell NB reconstitution was unclear
  3. 2000 High

    Multiple independent studies converged to establish PML as a central activator of p53 signaling: PML recruits p53 and CBP to NBs to drive p53 acetylation, promotes p53-dependent senescence downstream of oncogenic Ras, and is required for DNA-damage-induced p53 transcriptional activation and apoptosis.

    Evidence Co-IP, immunofluorescence, PML−/− MEF studies, retroviral overexpression, in vitro binding, reporter assays, epistasis with E1A (three independent labs)

    PMID:10910364 PMID:10950866 PMID:11025664

    Open questions at the time
    • The structural basis of the PML–p53 interaction was undefined
    • Whether p53 acetylation at K382 was sufficient or required additional PML-dependent modifications was unresolved
  4. 2000 High

    Demonstrating that PML is the master organizer of NB10-associated proteins (Daxx, Sp100) and that SUMO-1 modification controls the Daxx–NB equilibrium defined PML as the essential NB scaffold and SUMO as the key regulatory switch.

    Evidence PML reconstitution in PML−/− cells, cell fusion, immunofluorescence, SUMO modification studies

    PMID:10648561 PMID:10806078

    Open questions at the time
    • The oligomeric state of PML required for scaffolding was unknown
    • How SUMO modification mechanistically redirects Daxx between chromatin and NBs was not resolved
  5. 2002 Medium

    Placing PML downstream of ATM–Chk2 checkpoint signaling in p53-independent apoptosis broadened PML's role beyond p53 co-activation to a general DNA damage effector.

    Evidence Epistasis analysis with Chk2-deficient and PML-deficient cells, apoptosis assays after gamma irradiation

    PMID:12402044

    Open questions at the time
    • Direct phosphorylation of PML by Chk2 was not demonstrated
    • The specific PML domain mediating Chk2-dependent apoptosis was not mapped
  6. 2003 Medium

    Identification of a direct PML–MDM2 interaction, regulated by PML sumoylation, revealed a mechanism by which PML sequesters MDM2 to protect p53 from degradation, while MDM2 can reciprocally relocalize PML to the cytoplasm.

    Evidence In vitro binding, Co-IP, sumoylation mutants, subcellular localization, transcriptional reporter assay

    PMID:12759344

    Open questions at the time
    • In vivo physiological relevance of MDM2-mediated PML cytoplasmic redistribution was not shown
    • Whether MDM2 ubiquitinates PML directly was untested
  7. 2005 Medium

    Identifying SUMO-3 as specifically required for PML nuclear retention and NB integrity, distinct from SUMO-1, revealed SUMO paralog-specific regulation of NB biogenesis.

    Evidence siRNA depletion of individual SUMO isoforms, conjugation-defective mutants, immunoprecipitation

    PMID:15940266

    Open questions at the time
    • The SUMO-3-specific conjugation sites on PML were not mapped
    • Whether SUMO-3 oligomerization provides a physical scaffold versus a recruitment signal was unclear
  8. 2006 High

    Discovery that PML physically interacts with mTOR and displaces Rheb from mTOR in the nucleus connected PML to metabolic signaling, explaining how PML suppresses HIF-1α-driven angiogenesis.

    Evidence Co-IP, subcellular fractionation, Pml−/− mouse model, in vivo angiogenesis and rapamycin sensitivity assays

    PMID:16915281

    Open questions at the time
    • Whether PML directly competes with Rheb for mTOR binding or acts indirectly was not resolved structurally
    • The isoform specificity of PML–mTOR interaction was not defined
  9. 2006 High

    Demonstrating that PML bodies lose SUMO-1, Sp100, and Daxx during mitosis to form MAPPs that seed new NBs in G1 established the cell-cycle inheritance mechanism for nuclear bodies.

    Evidence Live cell imaging, FRAP, cell cycle synchronization, PML−/− rescue

    PMID:16492707

    Open questions at the time
    • The signal triggering MAPP-to-NB conversion in early G1 was unknown
    • Whether all PML isoforms equally contribute to MAPPs was not tested
  10. 2008 High

    Multiple 2008 studies defined the PML degradation cascade: CK2 phosphorylates PML at Ser517 to prime ubiquitin/proteasome-mediated turnover, and PML opposes HAUSP-mediated PTEN deubiquitination to control PTEN nuclear import, linking PML loss to PTEN cytoplasmic mislocalization in cancer.

    Evidence In vitro kinase assay, mutagenesis, degradation assays, xenograft models (CK2); Co-IP, siRNA, fractionation, drug treatment (PTEN/HAUSP)

    PMID:18566754 PMID:18716620

    Open questions at the time
    • Whether CK2 phosphorylation is the sole priming event or acts in concert with other kinases was not determined
    • The E3 ligase acting downstream of CK2 on wild-type PML was not identified at this point
  11. 2008 High

    Discovering that HDAC7 functions as a SUMO E3-like factor promoting PML sumoylation independently of deacetylase activity, and that PML stabilizes HIPK2/p300 by blocking SCF(Fbx3) ubiquitin ligase, expanded the network of PML-NB enzymatic activities.

    Evidence In vitro sumoylation reconstitution, Co-IP, HDAC7 knockdown (SUMO E3); complex purification, mass spectrometry, ubiquitination/degradation assays (HIPK2/p300)

    PMID:18625722 PMID:18809579

    Open questions at the time
    • Whether HDAC7 acts catalytically or stoichiometrically as a SUMO E3 was unclear
    • The structural basis of PML-mediated protection against SCF(Fbx3) was not defined
  12. 2010 Medium

    Showing that PML isoforms I and II confer intrinsic antiviral resistance against ICP0-null HSV-1 in a SUMO/SIM-dependent manner established PML-NBs as effectors of innate antiviral defense.

    Evidence siRNA depletion, individual isoform reconstitution, viral plaque assays, SUMO/SIM mutagenesis

    PMID:21172801

    Open questions at the time
    • Whether antiviral activity extends to wild-type HSV-1 bearing ICP0 was not addressed
    • The viral target(s) restricted by PML SUMO/SIM-dependent activity were not identified
  13. 2011 High

    Demonstrating that PML recruits E2F transcription factors together with Rb and heterochromatin proteins/PP1α to NBs to silence E2F-target genes provided the mechanistic link between PML, Rb pathway engagement, and irreversible senescence.

    Evidence ChIP, co-localization, dominant-negative Rb, E2F addback rescue, senescence assays

    PMID:21205865

    Open questions at the time
    • Whether PML-NB-associated heterochromatin formation is reversible was not tested
    • The specific PML isoform(s) mediating E2F sequestration were not identified
  14. 2011 Medium

    Identifying PML as required for Rad51, Mre11, BRCA1 foci formation and homology-directed repair after DSBs expanded PML function to direct participation in DNA damage repair.

    Evidence PML knockdown, immunofluorescence foci, HR reporter assay, Co-IP with Rad51, BrdU ssDNA detection

    PMID:21998700

    Open questions at the time
    • Whether PML promotes end-resection directly or via recruitment of resection factors was unclear
    • The PML domain required for Rad51 interaction was not mapped
  15. 2012 High

    PIAS1 was identified as a SUMO E3 ligase for PML that promotes CK2 interaction and subsequent proteasomal PML degradation, and RNF4 was shown to be the SUMO-targeted ubiquitin ligase required for arsenic-induced degradation of all PML isoforms, completing the SUMOylation→ubiquitination→degradation cascade.

    Evidence Co-IP, sumoylation assays, siRNA knockdown (PIAS1, RNF4), degradation assays, 3D-SIM super-resolution imaging

    PMID:22406621 PMID:24190887

    Open questions at the time
    • Whether RNF4 acts on endogenous PML under physiological (non-arsenic) conditions was not established
    • Other SUMO E3 ligases potentially redundant with PIAS1 were not excluded
  16. 2017 High

    Identification of CRL4(WDR4) as a novel E3 ubiquitin ligase for PML in lung cancer, whose activity promotes metastasis and immunosuppression, revealed a disease-relevant degradation pathway independent of SUMO-targeted mechanisms.

    Evidence Co-IP, ubiquitination assay, siRNA, xenograft and genetically engineered mouse models, flow cytometry for immune profiling

    PMID:28691927

    Open questions at the time
    • Whether CRL4(WDR4) acts on specific PML isoforms was not determined
    • The signal that activates CRL4(WDR4)-mediated PML degradation in cancer was not identified
  17. 2018 High

    Crystal structures of the PML RING tetramer and demonstration that tetramerization is required for UBC9 recruitment, PML sumoylation, NB assembly, and PML/RARα-driven leukemogenesis provided the first atomic-resolution understanding of NB biogenesis.

    Evidence X-ray crystallography, SAXS, in vitro sumoylation, mutagenesis, cell-based NB assays, transgenic mouse leukemia model

    PMID:29599493

    Open questions at the time
    • How the RING tetramer interfaces with the B1-box oligomer in full-length PML was not structurally resolved
    • The stoichiometry of UBC9 binding per RING tetramer was undefined
  18. 2018 High

    Large-scale SUMO proteomics showed that interferon-α-induced global cellular SUMOylation depends on PML (specifically isoforms III and IV), which recruits UBC9 to the nuclear matrix, establishing PML-NBs as a major hub for regulated SUMOylation.

    Evidence SUMO site proteomics, PML isoform reconstitution in PML-negative cells, subcellular fractionation, immunofluorescence

    PMID:29535160

    Open questions at the time
    • Whether PML-dependent SUMOylation is required for all IFN-induced antiviral effects was untested
    • The substrate selectivity mechanism for PML-promoted SUMOylation was not defined
  19. 2019 High

    Structural characterization of B1-box oligomerization via W157/F158/SD1 interfaces, and demonstration that disrupting this oligomerization abrogates sumoylation, NB biogenesis, and PML-RARα leukemogenesis, completed the two-step (RING tetramer → B1-box oligomer) model of NB assembly.

    Evidence X-ray crystallography (2.0 Å), SAXS, in vitro oligomerization, HeLa-Pml−/− reconstitution, transgenic mouse model, scRNA-seq

    PMID:31439836

    Open questions at the time
    • Full-length PML polymer structure remains unresolved
    • How B1-box oligomerization cooperates with SUMO-SIM interactions to drive phase separation is not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full structural model of intact PML nuclear bodies integrating RING tetramerization, B1-box oligomerization, SUMO-SIM network interactions, and the liquid-like or gel-like biophysical properties of the condensate remains to be determined.
  • No full-length PML polymer structure exists
  • The phase-separation versus ordered-scaffold model of NB assembly has not been resolved
  • Isoform-specific contributions to NB ultrastructure and partner recruitment are incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 5 GO:0005654 nucleoplasm 4 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2 R-HSA-73894 DNA Repair 1
Partners
CREBBPDAXXMDM2MTORPIAS1RB1TP53UBC9
Complex memberships
PML nuclear body

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 PML forms a trimeric complex with p53 and CBP acetyltransferase within PML nuclear bodies, facilitating CBP-mediated acetylation of p53 at lysine 382 in response to oncogenic Ras, an event required for p53-dependent senescence. PML-/- fibroblasts lose Ras-induced p53 acetylation and senescence. Co-immunoprecipitation, immunofluorescence co-localization, p53 acetylation assays in PML-/- cells, overexpression studies Nature High 10910364
2000 PML is induced by oncogenic Ras and promotes premature senescence by increasing p16, hypophosphorylated Rb, phospho-Ser15-p53, and p53 transcriptional targets. Forced PML expression drives p53 to PML oncogenic domains (PODs), and E1A abrogates PML-induced arrest. Retroviral overexpression, immunofluorescence, gene expression analysis, epistasis with E1A Genes & development High 10950866
2000 PML acts as a transcriptional co-activator with p53, physically interacting with p53 both in vitro and in vivo and co-localizing in PML-NBs. PML-/- primary cells show impaired p53-dependent DNA-damage-induced apoptosis, reduced p53 transcriptional activation, and decreased induction of Bax and p21 after gamma-irradiation. In vitro binding assay, Co-IP, immunofluorescence, reporter assays, PML-/- cell functional studies Nature cell biology High 11025664
2000 PML co-localizes and co-immunopurifies with eukaryotic initiation factor 4E (eIF-4E), and overexpression of PML causes nuclear retention of cyclin D1 mRNA and decreased cyclin D1 protein levels, requiring intact PML nuclear bodies. Addition of eIF-4E overcomes PML-induced mRNA retention. Co-immunoprecipitation, RNA localization assay, overexpression and rescue experiments Oncogene Medium 10763819
1998 PML forms stable complexes with the non-phosphorylated form of the retinoblastoma protein (pRB) within nuclear bodies; the B boxes and C-terminal region of PML are required for pRB binding. PML-pRB interaction abolishes glucocorticoid receptor-regulated transcriptional activation by pRB. Co-immunoprecipitation, co-localization, deletion mutagenesis, transcriptional reporter assays Molecular and cellular biology High 9448006
2006 PML physically interacts with mTOR, negatively regulates mTOR association with the GTPase Rheb by favouring mTOR nuclear accumulation, thereby repressing HIF-1α protein synthesis and neoangiogenesis. Pml-/- cells show higher sensitivity to rapamycin and elevated phospho-S6 levels. Co-immunoprecipitation, subcellular fractionation, in vivo angiogenesis assays, Pml-/- mouse model, rapamycin sensitivity assay Nature High 16915281
2008 PML nuclear bodies coordinate PTEN localization by opposing the deubiquitinylase HAUSP/USP7 through a PML-DAXX-HAUSP network; intact PML is required for PTEN nuclear entry. PML promotes PTEN nuclear localization, and HAUSP overexpression associates with PTEN nuclear exclusion in prostate cancer. Co-immunoprecipitation, subcellular fractionation, siRNA knockdown, functional localization assays, drug treatment (ATRA/arsenic trioxide) Nature High 18716620
2001 PML interacts with corepressors c-Ski, N-CoR, and mSin3A and with histone deacetylase 1, and this interaction is required for transcriptional repression mediated by the tumor suppressor Mad. PML-RARalpha inhibits Mad-mediated repression by aberrant binding to these corepressor complexes. Co-immunoprecipitation, transcriptional reporter assays, dominant-negative mutant studies Molecular cell Medium 11430826
2001 PML isoform I forms a specific complex with AML1 (RUNX1) and recruits AML1 and coactivator p300 to PML nuclear bodies, enhancing AML1-mediated transcription. A specific C-terminal region of PML I and AML1 are required for association and co-localization. Co-immunoprecipitation, immunofluorescence co-localization, transcriptional reporter assays, deletion mutagenesis Blood Medium 15331439
2002 The DNA damage checkpoint kinase hCds1/Chk2 mediates gamma irradiation-induced apoptosis in a p53-independent manner through an ATM-hCds1/Chk2-PML pathway, establishing PML as a downstream effector of checkpoint kinase signaling. Epistasis analysis, apoptosis assays, kinase activation assays, PML-deficient and Chk2-deficient cell studies Nature cell biology Medium 12402044
1999 PML and Sp100 undergo SUMO-1 conjugation during interphase and become de-conjugated during mitosis, with a mitosis-specific phosphorylated PML isoform appearing. Phosphatase inhibitors recapitulate mitotic PML modification in interphase cells, indicating phosphorylation regulates PML modification and ND10 composition across the cell cycle. Biochemical fractionation, immunofluorescence, phosphatase inhibitor treatment, cell cycle synchronization Journal of cell science Medium 10574707
2008 Casein kinase 2 (CK2) directly phosphorylates PML at Ser517, priming ubiquitin/proteasome-mediated PML degradation. PML mutants resistant to CK2 phosphorylation display increased tumor suppressive functions in apoptosis, senescence, and xenograft assays. In vitro kinase assay, mutagenesis, degradation assays, functional apoptosis/senescence assays, xenograft models Molecular and cellular biochemistry High 18566754
2012 The SUMO E3-ligase PIAS1 sumoylates PML, promoting CK2 interaction and subsequent ubiquitin/proteasome-mediated PML degradation, attenuating its tumor suppressor functions. PIAS1-mediated SUMOylation of PML-RARA is also essential for arsenic trioxide-induced degradation of the fusion oncoprotein. Co-immunoprecipitation, sumoylation assays, siRNA knockdown, degradation assays, apoptosis assays Cancer research High 22406621
2008 HDAC7 promotes PML sumoylation independently of its HDAC enzymatic activity; HDAC7 associates with the SUMO E2 ligase Ubc9 and stimulates PML sumoylation in vitro, acting as a SUMO E3 ligase-like factor essential for PML nuclear body formation. HDAC7 knockdown, in vitro sumoylation assay, Co-immunoprecipitation, immunofluorescence Molecular and cellular biology High 18625722
2005 SUMO-3 covalently modifies PML and is specifically required (unlike SUMO-1 or SUMO-2) for PML nuclear localization and nuclear body integrity; oligomerization of SUMO-3 is required for PML nuclear retention, as shown by siRNA depletion and expression of conjugation-defective mutants. siRNA knockdown, immunoprecipitation, rescue with SUMO isoforms, SUMO conjugation-defective mutants Oncogene Medium 15940266
2010 SIRT1 stabilizes PML protein and stimulates PML sumoylation both in vitro and in vivo in a deacetylase-independent manner, thereby controlling PML-NB integrity and antiviral apoptotic responses. In vitro sumoylation assay, SIRT1 KO mouse embryo fibroblasts, SIRT1 knockdown, overexpression, viral infection assays Cell death and differentiation Medium 20577263
2018 PML RING domain tetramerizes through PML-specific sequences, and this tetramerization is required for nuclear body assembly, PML sumoylation (via UBC9/SUMO E2 recruitment), and PML/RARA-driven leukemogenesis. Crystal structure and SAXS characterization define the tetrameric interface. X-ray crystallography, SAXS, in vitro sumoylation assay, mutagenesis, cell-based NB formation assay, transgenic mouse leukemia model Nature communications High 29599493
2019 PML B1-box forms a specific oligomeric network via W157-, F158-, and SD1-interfaces; B1-box oligomerization is required for PML sumoylation and nuclear body biogenesis in cells, and the B1-box F158E mutation prevents PML-RARα-driven leukemogenesis in transgenic mice. X-ray crystallography (2.0 Å), SAXS, in vitro oligomerization assays, mutagenesis, HeLa-Pml-/- cell reconstitution, transgenic mouse model, single-cell RNA sequencing Nature communications High 31439836
2000 PML nuclear bodies are protein-based structures (~250 nm) devoid of nucleic acid at their core; newly synthesized RNA associates only with the periphery of PML bodies. This demonstrates PML NBs are not sites of active transcription but may facilitate a favorable nuclear environment for gene expression. Electron spectroscopic imaging (ESI), analytical transmission electron microscopy The Journal of cell biology High 10648561
2000 PML is critical for proper localization of all other ND10-associated proteins; introducing PML into PML-/- cells recruits ND10-associated proteins (including Daxx and Sp100) to de novo formed ND10. SUMO-1 modification of PML controls the equilibrium of Daxx between condensed chromatin and ND10. Cell fusion, transient transfection in PML-/- cells, immunofluorescence, SUMO-1 modification studies Journal of structural biology High 10806078
2008 PML isoforms exhibit individual exchange rates at PML-NBs; PML isoform V serves as a scaffold subunit with slowest exchange. SUMOylation modulates turnover dynamics of PML and SP100. HIPK2 requires active kinase for PML-NB targeting. Elevated PML IV increases HIPK2 residence time. DAXX and BLM turn over rapidly (seconds) at PML-NBs. Live cell imaging, FRAP, mathematical modeling of exchange kinetics Journal of cell science High 18664490
2006 During mitosis, PML nuclear bodies lose SUMO-1, Sp100, and Daxx and partition as mitotic accumulations of PML protein (MAPPs), a subset of which associates with mitotic chromosomes providing nucleation sites for PML-NB re-formation in G1. PML protein from MAPPs is recycled (not degraded) to form new nuclear bodies in daughter nuclei. Live cell imaging, FRAP, immunofluorescence, cell cycle synchronization, PML-/- rescue Journal of cell science High 16492707
2003 PML physically interacts with MDM2 in vivo and in vitro through two independent interaction regions. PML sumoylation at K160 negatively regulates PML-MDM2 binding. MDM2 co-expression redistributes PML from nucleus to cytoplasm via interaction between PML N-terminus and MDM2 RING domain. MDM2 inhibits PML-mediated CBP transcriptional co-activation via its acidic domain. In vitro binding assay, Co-IP, subcellular localization studies, sumoylation mutants, transcriptional reporter assay The Journal of biological chemistry Medium 12759344
2008 PML inhibits degradation of HIPK2 and p300 by blocking SCF(Fbx3) ubiquitin ligase-mediated proteasomal degradation without preventing their ubiquitination, thereby stabilizing the p53 transcriptional complex. PML, Fbx3, and HIPK2 synergistically activate p53-induced transcription. PML complex purification, mass spectrometry, ubiquitination assays, degradation assays, transcriptional reporter assays Molecular and cellular biology High 18809579
2012 PML acts as a negative regulator of PGC1A acetylation and a potent activator of PPAR signaling and fatty acid oxidation in breast cancer cells. PML promotes ATP production and inhibits anoikis, and this activity is dependent on cytoplasmic PML function. PGC1A acetylation assays, PPAR reporter assays, fatty acid oxidation assays, 3D basement membrane culture models, pharmacological inhibition The Journal of clinical investigation Medium 22886304
2011 PML induces permanent cell cycle exit and senescence by recruiting E2F transcription factors (bound to promoters) and Rb proteins to PML nuclear bodies enriched in heterochromatin proteins and protein phosphatase 1α. Blocking Rb family functions or adding back E2Fs rescues E2F-dependent gene expression and cell proliferation. ChIP, co-localization, dominant-negative Rb, E2F addback rescue, senescence assays Genes & development High 21205865
2011 PML physically interacts with the clock protein PER2 and is required for PER2 nuclear localization; in Pml-/- cells PER2 distribution is primarily perinuclear/cytoplasmic. PML is acetylated at K487, and SIRT1-mediated deacetylation of PML promotes its control of PER2 nuclear localization and circadian clock function. Co-IP, immunofluorescence in Pml-/- SCN and MEFs, acetylation assay, SIRT1 functional studies, circadian period analysis The EMBO journal Medium 22274616
2010 PML isoforms I and II partially restore cellular resistance to ICP0-null mutant HSV-1 in PML-depleted cells. Antiviral activity of PML isoform I requires SUMO modification, its SUMO interaction motif (SIM), and each element of its TRIM domain. siRNA depletion, individual isoform expression, viral plaque assays, SUMO/SIM mutagenesis Journal of cell science Medium 21172801
2011 PML is required for the formation of Rad51, Mre11, and BRCA1 foci after DNA double-strand breaks and is required for homology-directed repair. PML physically associates with Rad51 after DNA damage. PML depletion abrogates RPA foci formation and ssDNA generation, and prevents Chk1 activation after gamma-irradiation. PML knockdown, immunofluorescence foci assays, HR reporter assay, Co-IP, BrdU ssDNA detection, Chk1 activation assay PloS one Medium 21998700
2006 Poliovirus infection induces PML phosphorylation via the ERK pathway, increases PML SUMOylation, and triggers PML transfer from nucleoplasm to nuclear matrix, leading to p53 recruitment to PML NBs, p53 phosphorylation on Ser15, and activation of p53 target genes promoting apoptosis as an antiviral defense. Phosphorylation assays, SUMOylation assays, immunofluorescence, siRNA knockdown of p53, viral replication assays Journal of virology Medium 16912307
2017 WDR4-containing CRL4 ubiquitin ligase (CRL4WDR4) mediates PML ubiquitination and degradation in lung cancer. This PML degradation pathway induces CD73, uPAR, and SAA2 expression to promote tumor cell migration, invasion, metastasis, and immunosuppression (elevated Tregs, M2 macrophages, reduced CD8+ T cells). Co-IP, ubiquitination assay, siRNA knockdown, xenograft models, genetically engineered mouse models, flow cytometry The Journal of clinical investigation High 28691927
2013 PML body assembly dynamics assessed by high-resolution 3D structured illumination show PML forms spherical shells with associated SUMO. Arsenic treatment induces isoform-specific changes to PML body ultrastructure. All PML isoforms are modified by SUMO and ubiquitin after arsenic treatment, and arsenic-induced degradation of all isoforms requires the SUMO-targeted ubiquitin E3 ligase RNF4. 3D structured illumination microscopy, siRNA (RNF4 depletion), immunoprecipitation, high-content imaging assay Journal of cell science High 24190887
2018 Interferon-α treatment increases global cellular SUMOylation in a PML-dependent manner, requiring PML isoforms III and IV specifically. PML promotes IFN-induced UBC9 (SUMO E2) transfer to the nuclear matrix where it colocalizes with PML within NBs, enhancing cellular SUMOylation. Large-scale proteomics (SUMO site identification), PML isoform reconstitution in PML-negative cells, fractionation, immunofluorescence Molecular & cellular proteomics High 29535160
2002 PML forms a complex with STAT3 through its B-box and C-terminal regions both in vitro and in vivo, inhibiting STAT3 DNA-binding activity and STAT3-dependent cell growth. PML/RARα dissociates PML from STAT3, restoring STAT3 activity. In vitro binding assay, Co-IP, DNA-binding assay (EMSA), reporter assay, growth assay with Ba/F3 cells Blood Medium 12506013
2009 Telomeric DNA serves as a nucleation site for de novo PML body formation during interphase. SMC5 (a component of the SUMO ligase MMS21-containing SMC5/6 complex) localizes transiently at telomeric DNA during PML body formation, suggesting SUMO modification at telomeres drives PML body biogenesis. Live cell imaging, immunofluorescence, telomere localization assays Molecular biology of the cell Medium 19793919
2019 Mad1 directly interacts with PML (interaction enhanced by sumoylation) and localizes to PML nuclear bodies. Upregulated Mad1 displaces MDM2 from PML, preventing PML-mediated MDM2 sequestration to the nucleolus, thereby freeing MDM2 to ubiquitinate and destabilize p53. Co-IP, proximity ligation assay, sumoylation-enhanced interaction assay, MDM2 localization studies, orthotopic mammary tumor model Nature communications Medium 30948704
2008 ZIP kinase (ZIPK) resides in PML oncogenic domains (PODs), where it colocalizes with and binds proapoptotic protein Daxx. ZIPK recruits Daxx to PODs via its catalytic kinase activity; kinase-inactive ZIPK prevents Daxx association with PODs. ZIPK also binds and phosphorylates Par-4, and association with Daxx is enhanced by Par-4 coexpression, mediating nuclear apoptosis. Co-immunoprecipitation, immunofluorescence, kinase assays, siRNA knockdown, caspase activation assays Molecular and cellular biology Medium 12917339

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 699 10910364
2000 The transcriptional role of PML and the nuclear body. Nature cell biology 476 10806494
2010 PML nuclear bodies. Cold Spring Harbor perspectives in biology 454 20452955
2008 The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature 453 18716620
2002 The role of PML in tumor suppression. Cell 452 11832207
2000 PML is induced by oncogenic ras and promotes premature senescence. Genes & development 405 10950866
2000 The function of PML in p53-dependent apoptosis. Nature cell biology 396 11025664
2001 PML protein isoforms and the RBCC/TRIM motif. Oncogene 381 11704850
2004 PML nuclear bodies: dynamic sensors of DNA damage and cellular stress. BioEssays : news and reviews in molecular, cellular and developmental biology 333 15351967
2006 PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature 319 16915281
2000 Review: properties and assembly mechanisms of ND10, PML bodies, or PODs. Journal of structural biology 238 10806078
2012 A metabolic prosurvival role for PML in breast cancer. The Journal of clinical investigation 233 22886304
2000 Promyelocytic leukemia (PML) nuclear bodies are protein structures that do not accumulate RNA. The Journal of cell biology 223 10648561
2001 DNA viruses and viral proteins that interact with PML nuclear bodies. Oncogene 217 11704855
2002 PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Nature cell biology 194 12402044
2004 Establishment of papillomavirus infection is enhanced by promyelocytic leukemia protein (PML) expression. Proceedings of the National Academy of Sciences of the United States of America 193 15383670
2008 Dynamics of component exchange at PML nuclear bodies. Journal of cell science 173 18664490
1999 Cell cycle regulation of PML modification and ND10 composition. Journal of cell science 164 10574707
1995 PML nuclear bodies are general targets for inflammation and cell proliferation. Cancer research 146 7882370
2004 PML nuclear bodies and apoptosis. Oncogene 143 15077145
2016 Emerging Role of PML Nuclear Bodies in Innate Immune Signaling. Journal of virology 142 27053550
1998 The promyelocytic leukemia gene product (PML) forms stable complexes with the retinoblastoma protein. Molecular and cellular biology 139 9448006
2013 Differential Roles of PML Isoforms. Frontiers in oncology 132 23734343
2011 Regulation of E2Fs and senescence by PML nuclear bodies. Genes & development 132 21205865
2008 Regulation of apoptosis by PML and the PML-NBs. Oncogene 127 18931695
2001 Role of PML and PML-RARalpha in Mad-mediated transcriptional repression. Molecular cell 125 11430826
1999 The PML nuclear bodies: actors or extras? Current opinion in genetics & development 116 10377280
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