Affinage

PML

Protein PML · UniProt P29590

Length
882 aa
Mass
97.6 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PML is the essential scaffold of PML nuclear bodies (ND10), subnuclear protein-based structures that concentrate partner proteins to control their post-translational modification, stability, and localization; introducing PML into PML-null cells recruits ND10-associated proteins such as Daxx and Sp100, and increased SUMO-1 modification of PML drives this recruitment (PMID:10806078). Body biogenesis depends on sequential B1-box-mediated oligomerization of the PML RBCC domain (monomer→dimer→tetramer→N-mer), and B1-interface mutations abolish PML SUMOylation and nuclear-body formation (PMID:31439836); the body core is a dense protein structure that excludes nucleic acid and is not a site of transcription (PMID:10648561). PML SUMOylation is the central regulatory switch governing partner recruitment, and is stimulated by accessory factors including HDAC7 and SIRT1, both of which control PML body size and number (PMID:18625722, PMID:20577263). Through these bodies PML potentiates p53 function, acting as a p53 transcriptional co-activator required for p53 target induction after gamma-irradiation (PMID:11025664) and coupling reactive oxygen species sensing to p53 activation, with Pml-null animals failing to mount oxidative-stress-responsive p53 programs (PMID:28931625); it likewise enforces senescence by sequestering E2F/Rb complexes at heterochromatin-enriched bodies (PMID:21205865) and contributes to homologous recombination repair by enabling Rad51, Mre11, BRCA1, and RPA focus formation and DSB processing (PMID:21998700). PML also functions outside the body and nucleus: cytoplasmic PML scaffolds Smad2/3-SARA complexes at early endosomes to transduce TGF-β signaling (PMID:15356634), represses mTOR by promoting its nuclear sequestration away from Rheb (PMID:16915281), and supports antiviral and antibacterial restriction through Daxx stabilization and oxidation-triggered de-SUMOylation (PMID:26566030, PMID:28074026). In acute promyelocytic leukemia the t(15;17) PML-RARα fusion retains RARα DNA- and retinoid-binding regions while losing the RARα transactivation domain (PMID:1650447); arsenic trioxide induces PML SUMOylation that triggers RNF4-dependent K48 polyubiquitination and proteasomal degradation of PML and PML-RARα, underpinning the therapeutic response, and PML function is required for retinoic-acid-induced differentiation and tumor suppression (PMID:18408733, PMID:9488655).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1991 Medium

    Defining the molecular nature of the APL fusion oncoprotein established that PML-RARα is an aberrant retinoid receptor, framing PML's relevance to leukemia.

    Evidence cDNA cloning, retinoid-binding and transactivation assays of the t(15;17) fusion

    PMID:1650447

    Open questions at the time
    • Did not address normal PML function
    • No structural mechanism for how the fusion subverts PML bodies
  2. 1998 High

    Knockout of PML placed it as an essential effector of retinoic-acid-induced differentiation and tumor suppression, establishing physiological function beyond the fusion.

    Evidence Murine PML knockout, myeloid differentiation, RA-dependent p21 transactivation and tumorigenesis assays

    PMID:9488655

    Open questions at the time
    • Mechanism by which PML enables RA transactivation not resolved
    • Did not establish the body-level mechanism
  3. 2000 Medium

    Reconstitution in PML-null cells showed PML is the organizer that recruits all other ND10 components, defining its scaffold role and the SUMO-dependence of partner recruitment.

    Evidence Transfection/cell-fusion in PML-/- cells, immunofluorescence, SUMO-1 overexpression

    PMID:10806078

    Open questions at the time
    • SUMO E3 machinery for PML not identified here
    • Quantitative oligomerization mechanism unknown
  4. 2000 High

    Structural imaging established that PML body cores are protein-based and nucleic-acid-free, falsifying the prior model that bodies are transcription/RNA-accumulation sites.

    Evidence Electron spectroscopic imaging and 5-bromouridine RNA labeling

    PMID:10648561

    Open questions at the time
    • Did not define the molecular assembly principle of the core
    • Function of peripheral RNA association left open
  5. 2000 High

    Demonstrating that PML co-activates p53 connected the bodies to a tumor-suppressor transcriptional program engaged after DNA damage.

    Evidence GST pulldown, in vivo Co-IP, PML-/- cell transcription and apoptosis assays after gamma-irradiation

    PMID:11025664

    Open questions at the time
    • Whether co-activation requires SUMO-dependent recruitment not shown
    • Direct enzymatic role on p53 not defined
  6. 2002 Medium

    PML was placed in a p53-independent DNA-damage apoptotic arm and shown to restrain STAT3, broadening its role to checkpoint signaling and cytokine response.

    Evidence ATM-Chk2 epistasis with PML-null cells; PML-STAT3 Co-IP, EMSA, Ba/F3 growth assays

    PMID:12402044 PMID:12506013

    Open questions at the time
    • Direct biochemical link between Chk2 and PML not resolved
    • How PML body localization gates STAT3 inhibition unclear
  7. 2004 High

    Identification of a cytoplasmic PML pool scaffolding Smad2/3-SARA at endosomes established a non-nuclear signal-transduction function in TGF-β responses.

    Evidence Co-IP, Pml-null primary cell phenotyping, endosomal fractionation, cytoplasmic PML rescue

    PMID:15356634

    Open questions at the time
    • Determinants of nuclear vs cytoplasmic PML partitioning not defined
    • Structural basis of Smad/SARA scaffolding unknown
  8. 2006 High

    PML was shown to suppress mTOR by promoting its nuclear sequestration away from Rheb, linking the bodies to translational/hypoxic control.

    Evidence PML-mTOR Co-IP, Pml-null tumors, rapamycin sensitivity and S6 phosphorylation, in vivo tumor models

    PMID:16915281

    Open questions at the time
    • How PML physically retains mTOR in the nucleus not detailed
    • Relationship to NB SUMOylation switch unclear
  9. 2008 High

    Arsenic-induced PML SUMOylation was shown to recruit RNF4 and drive K48 polyubiquitination and proteasomal degradation of PML/PML-RARα, providing the molecular basis for APL therapy.

    Evidence Reciprocal Co-IP, dominant-negative RNF4, SUMO-site mutants, ubiquitination and differentiation assays

    PMID:18408733

    Open questions at the time
    • Stoichiometry/site specificity of the SUMO-ubiquitin handoff not fully mapped
  10. 2008 Medium

    Multiple 2008 studies expanded PML's modification-control logic: it gates PTEN nuclear trafficking via DAXX/HAUSP, protects HIPK2/p300 from SCFFbx3 degradation, and depends on HDAC7 for body-forming SUMOylation.

    Evidence Co-IP, ubiquitylation assays, fractionation, MS-based complex purification, in vitro SUMOylation, knockdowns

    PMID:18625722 PMID:18716620 PMID:18809579

    Open questions at the time
    • Each interaction characterized in single labs
    • How a single scaffold coordinates so many distinct modification outcomes unresolved
  11. 2011 Medium

    PML was integrated into homologous-recombination repair and senescence enforcement, showing the bodies physically organize repair factors and E2F/Rb-driven cell-cycle exit.

    Evidence PML knockdown with Rad51/Mre11/BRCA1/RPA foci and HR reporter assays; ChIP/Co-IP of E2F-Rb recruitment with senescence rescue

    PMID:21205865 PMID:21998700

    Open questions at the time
    • Whether PML acts directly on repair complexes or via sequestration unclear
    • Causal order of body assembly vs senescence entry not resolved
  12. 2019 High

    Structural and mutagenesis work defined the B1-box oligomerization interfaces required for SUMOylation and body biogenesis, and showed disrupting them blocks PML-RARα leukemogenesis in vivo.

    Evidence 2.0 Å crystal structure, SAXS, B1-interface mutagenesis, NB reconstitution in HeLaPML-/-, transgenic mouse model

    PMID:31439836

    Open questions at the time
    • How oligomerization couples to the SUMO E2/E3 reaction mechanistically not fully defined
  13. 2022 Medium

    Neddylation of the RARα moiety was shown to impede PML phase separation and body assembly, with deneddylation (MLN4924) restoring functional bodies and suppressing leukemia, adding a phase-behavior layer to APL biology.

    Evidence Neddylation site mapping, phase separation and DNA-binding assays, NB reconstitution, MLN4924 in APL mouse models

    PMID:35194189

    Open questions at the time
    • In-cell evidence for endogenous PML phase separation limited
    • Single-lab characterization

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many PML isoforms and the SUMOylation/oligomerization/phase-separation switches are integrated to select among the protein's diverse outputs (p53 co-activation, mTOR suppression, TGF-β transduction, repair, immune restriction) remains unresolved.
  • No unified model linking isoform identity to specific functional output
  • Mechanism that partitions nuclear vs cytoplasmic PML pools undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140110 transcription regulator activity 3 GO:0060090 molecular adaptor activity 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0043226 organelle 2 GO:0005768 endosome 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-162582 Signal Transduction 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
DAXXMTORP53RAD51RNF4SMAD2/3STAT3TET2
Complex memberships
PML nuclear body (ND10)SCF(Fbx3) ubiquitin ligase complexSmad2/3-SARA endosomal complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Arsenic trioxide induces PML SUMOylation, which triggers Lys48-linked polyubiquitination of PML and recruits RNF4 (the human orthologue of the yeast SUMO-dependent E3 ubiquitin ligase) to PML nuclear bodies, leading to proteasome-dependent degradation of PML and PML-RARα. SUMOylated PML also recruits ubiquitin and proteasomes onto PML nuclear bodies. A dominant-negative RNF4 impairs arsenic-induced differentiation, directly implicating PML-RARα catabolism in the therapeutic response. Co-immunoprecipitation, dominant-negative RNF4 expression, SUMOylation mutant analysis, ubiquitination assays, cell differentiation assays Nature cell biology High 18408733
2008 PML nuclear bodies coordinate PTEN localization by opposing the deubiquitylating enzyme HAUSP/USP7 through a mechanism involving the adaptor protein DAXX. PML opposes HAUSP-mediated deubiquitylation of PTEN, which is required for PTEN nuclear entry. This PML-DAXX-HAUSP network controls PTEN subcellular trafficking and is disrupted by the PML-RARα oncoprotein. Co-immunoprecipitation, knockdown/knockout studies, ubiquitylation assays, nuclear/cytoplasmic fractionation, rescue experiments with ATRA/arsenic trioxide Nature High 18716620
2004 Cytoplasmic PML isoforms are essential modulators of TGF-β signaling. Cytoplasmic PML physically interacts with Smad2/3 and SARA (Smad anchor for receptor activation) and is required for Smad2/3 phosphorylation, nuclear translocation, SARA association, and accumulation of SARA and TGF-β receptor in early endosomes. PML-null primary cells are resistant to TGF-β-dependent growth arrest, senescence, and apoptosis. Co-immunoprecipitation, Pml-null primary cell phenotyping, Smad2/3 phosphorylation assays, endosomal fractionation, cytoplasmic PML expression rescue Nature High 15356634
2006 PML inhibits HIF-1α synthesis under hypoxic conditions by repressing mTOR. PML physically interacts with mTOR and negatively regulates mTOR association with the small GTPase Rheb by promoting mTOR nuclear accumulation. Pml−/− cells and tumours display higher sensitivity to rapamycin and lack of PML inversely correlates with phosphorylation of ribosomal protein S6. Co-immunoprecipitation (PML-mTOR), Pml-null cell/tumour analysis, rapamycin sensitivity assays, subcellular fractionation showing mTOR nuclear accumulation, in vivo tumour models Nature High 16915281
2000 PML physically interacts with p53 both in vitro and in vivo, co-localizes with p53 in PML nuclear bodies, and acts as a transcriptional co-activator for p53. PML-dependent p53-DNA binding activity, p53 transcriptional activation, and induction of p53 target genes (Bax, p21) upon gamma-irradiation are all impaired in Pml−/− primary cells. In vitro GST pulldown, co-immunoprecipitation in vivo, co-localization by immunofluorescence, Pml−/− cell apoptosis and transcription assays, gamma-irradiation Nature cell biology High 11025664
1998 PML function is essential for the tumor-growth-suppressive activity of retinoic acid (RA) and for RA-induced terminal myeloid differentiation. PML is required for RA-dependent transactivation of the p21WAF1/CIP1 gene, placing PML as a critical component of the RA signaling pathway. Homologous recombination knockout of murine PML, hematopoietic differentiation assays, RA-dependent p21 transactivation assays, tumorigenesis assays Science High 9488655
2001 PML interacts with multiple corepressors (c-Ski, N-CoR, mSin3A) and histone deacetylase 1, and this interaction is required for transcriptional repression mediated by the tumor suppressor Mad. PML-RARα, which has two corepressor-interacting sites, inhibits Mad-mediated repression, suggesting aberrant binding to corepressor complexes contributes to leukemogenesis. Co-immunoprecipitation, transcriptional reporter assays, domain mapping Molecular cell Medium 11430826
1998 PML colocalizes with the non-phosphorylated fraction of the retinoblastoma protein (pRB) in nuclear bodies. Both PML and PML-RARα form complexes with the non-phosphorylated form of pRB in vivo and interact with the pRB pocket region. The B boxes and C-terminal region of PML are essential for stable complex formation. PML abolishes glucocorticoid receptor-regulated transcription activation by pRB. Co-immunoprecipitation, co-localization immunofluorescence, domain deletion mutant analysis, transcriptional reporter assays Molecular and cellular biology Medium 9448006
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. PML functions downstream of ATM-hCds1/Chk2 in this pathway, defining PML's role in the p53-independent apoptotic arm of the DNA damage response. Genetic epistasis in cell lines, gamma irradiation apoptosis assays, kinase activity assays, PML-null cell studies Nature cell biology Medium 12402044
2003 PML physically interacts with MDM2 in vivo and in vitro through two separate regions: PML residues 300–633 interact with the MDM2 acidic domain, and PML residues 1–200 (RING/B-box region) interact with the MDM2 C-terminal RING domain. MDM2 coexpression redistributes PML from nucleus to cytoplasm via interaction with the PML N-terminus and MDM2 RING domain. MDM2 inhibits PML-stimulated transcriptional activation of CBP. PML SUMOylation at K160 negatively regulates PML-MDM2 binding. Co-immunoprecipitation in vivo, GST pulldown in vitro, domain deletion mutants, subcellular fractionation, transcriptional reporter assays The Journal of biological chemistry Medium 12759344
2008 PML activates transcription by protecting HIPK2 and p300 from SCFFbx3-mediated ubiquitin-proteasomal degradation. PML forms a complex containing Fbx3, Skp1, and Cullin1 (SCFFbx3 ubiquitin ligase). PML inhibits degradation of HIPK2 and p300 without inhibiting their ubiquitination, and PML/Fbx3/HIPK2 synergistically activate p53-induced transcription. PML-RARα instead promotes HIPK2 degradation. PML complex purification and mass spectrometry identification, co-immunoprecipitation, ubiquitination assays, transcriptional reporter assays, proteasome inhibitor studies Molecular and cellular biology Medium 18809579
2008 HDAC7 promotes PML SUMOylation essential for PML nuclear body formation. HDAC7 associates with the SUMO E2 ligase Ubc9 and stimulates PML SUMOylation in vitro, acting with SUMO E3 ligase-like activity. HDAC7 knockdown reduces PML nuclear body size and number and inhibits TNF-α-induced PML SUMOylation in HUVECs. HDAC7 knockdown (siRNA), in vitro SUMOylation assay, co-immunoprecipitation, immunofluorescence of PML bodies Molecular and cellular biology Medium 18625722
2000 PML is critical for proper localization of all other ND10/PML-body-associated proteins. Introducing PML into PML−/− cells recruits ND10-associated proteins (including Daxx, Sp100) into de novo formed ND10 bodies. Increased SUMO-1 modification of PML segregates Daxx from condensed chromatin to ND10, demonstrating that SUMO-1 modification of PML controls recruitment of partner proteins. Transient transfection in PML−/− cells, cell fusion experiments, immunofluorescence, SUMO-1 overexpression Journal of structural biology Medium 10806078
1999 PML and Sp100 are conjugated to SUMO-1 during interphase but become de-conjugated during mitosis. A mitosis-specific PML isoform of distinct electrophoretic mobility appears that is stabilized by phosphatase inhibitors, indicating phosphorylation is an important modifier of PML during the cell cycle. Treatment with phosphatase inhibitors in interphase cells induces PML isoforms resembling the mitotic form and causes structural changes in ND10. Cell cycle synchronization, immunoblotting for SUMO-1-conjugated PML, phosphatase inhibitor treatment, immunofluorescence of PML bodies Journal of cell science Medium 10574707
2000 PML nuclear body core is a dense, protein-based structure (~250 nm diameter) that does not contain detectable nucleic acid (no RNA or chromatin). Newly synthesized RNA is associated with the periphery of PML nuclear bodies, not within the protein core. These bodies are not sites of transcription. Electron spectroscopic imaging (ESI) analytical transmission electron microscopy, 5-bromouridine RNA labeling The Journal of cell biology High 10648561
2008 PML and YAP physically interact through PML's PVPVY motif and YAP's WW domain. PML-mediated SUMOylation stabilizes YAP. PML is a direct transcriptional target of p73/YAP, forming a proapoptotic autoregulatory feedback loop. Akt/PKB kinase negatively controls PML transcriptional activation by p73/YAP. Co-immunoprecipitation, domain mutant analysis (PVPVY/WW), SUMOylation assays, transcriptional reporter assays, Akt inhibitor studies Molecular cell Medium 19111660
2002 PML forms a complex with STAT3 through its B-box and C-terminal regions in vitro and in vivo, inhibiting STAT3 DNA-binding activity. PML-RARα dissociates PML from STAT3 and restores STAT3 activity. In cells dependent on gp130/STAT3-mediated growth, PML abrogates proliferation while PML-RARα enhances it. Co-immunoprecipitation, GST pulldown, luciferase transcription assays, EMSA for STAT3 DNA binding, Ba/F3 cell growth assays Blood Medium 12506013
2003 ZIP kinase (ZIPK) is present in PML nuclear bodies (PODs) and colocalizes with and binds to proapoptotic protein Daxx. Arsenic trioxide and IFN-γ increase the association of ZIPK with PODs. Kinase-inactive ZIPK has diffuse nuclear localization and prevents Daxx association with PODs, indicating ZIPK recruits Daxx via its catalytic activity. ZIPK also binds and phosphorylates Par-4; siRNA knockdown of ZIPK, Daxx, or Par-4 decreases caspase activation and apoptosis induced by arsenic/IFN-γ. Co-immunoprecipitation, immunofluorescence co-localization, kinase-dead mutant analysis, siRNA knockdown, caspase activity assays Molecular and cellular biology Medium 12917339
2010 PML isoforms I and II partially restore restriction of ICP0-null mutant HSV-1 replication in PML-depleted cells. The antiviral activity of PML isoform I requires its SUMO modification, its SUMO interaction motif (SIM), and each element of its TRIM domain. Deletion of the SIM motif from PML isoform I increases colocalization with other major ND10 components. Individual PML isoform expression in PML-depleted cells, viral plaque assays, SUMO modification site mutagenesis, SIM deletion mutants, immunofluorescence Journal of cell science Medium 21172801
2010 SIRT1 stabilizes PML protein and stimulates PML SUMOylation in vitro and in vivo in a deacetylase-independent manner. SIRT1 knockdown reduces PML protein levels, PML nuclear body size and number. SIRT1 absence reduces the apoptotic response to VSV infection and favors PML-sensitive virus replication. In vitro SUMOylation assay, SIRT1 knockdown (shRNA/siRNA), SIRT1 knockout MEFs, immunofluorescence of PML bodies, viral replication assay Cell death and differentiation Medium 20577263
2011 PML induces a permanent cell cycle exit and activates p53 and senescence by recruiting E2F transcription factors (bound to their promoters) and Rb proteins to PML nuclear bodies enriched in heterochromatin proteins and protein phosphatase 1α. Blocking Rb family function or adding back E2Fs rescues E2F-dependent gene expression and proliferation, inhibiting the senescent phenotype. Immunoprecipitation, immunofluorescence, chromatin immunoprecipitation (ChIP), Rb functional blockade, E2F rescue experiments, cell proliferation assays Genes & development Medium 21205865
2012 PML protein physically interacts with PER2 and is expressed in a circadian manner in the suprachiasmatic nucleus (SCN). Loss of PML disrupts expression of clock regulators (Per2, Per1, Cry1, Bmal1, Npas2), and in Pml−/− cells PER2 distribution is primarily perinuclear/cytoplasmic rather than nuclear. PML is acetylated at K487, and its deacetylation by SIRT1 promotes PML control of PER2 nuclear localization. In Pml−/− mice, circadian period shows reduced precision and stability. Co-immunoprecipitation (PML-PER2), Pml−/− mouse circadian phenotyping, immunofluorescence/subcellular fractionation of PER2, acetylation site mutagenesis (K487), SIRT1 deacetylation assay The EMBO journal Medium 22274616
2015 PML/TRIM19 inhibits retroviral (HIV-1) reverse transcription indirectly through stabilization of Daxx. In the presence of PML, cytoplasmic Daxx is found in the vicinity of incoming HIV-1 capsids and inhibits reverse transcription. HIV-1 infection triggers formation of PML cytoplasmic bodies within 30 min, peaking at ~2 h post-infection. PML re-localization is blocked by reverse-transcription inhibitors. PML knockdown (siRNA), quantitative RT-PCR of HIV cDNA intermediates, immunofluorescence of PML cytoplasmic bodies, reverse-transcription inhibitor treatment, Daxx depletion experiments PLoS pathogens Medium 26566030
2011 PML is functionally connected to the homologous recombination (HR) repair machinery. PML depletion abrogates Rad51, Mre11, BRCA1, and RPA foci following DNA damage. PML associates with Rad51 following LT expression or external DNA damage. PML-depleted cells fail to generate ssDNA foci or activate Chk1 upon gamma-irradiation, indicating PML is required for DSB processing. PML is also required for HR-mediated repair as measured by a direct HR assay. PML knockdown (siRNA), immunofluorescence for DNA repair foci, Co-immunoprecipitation (PML-Rad51), HR reporter assay, BrdU incorporation (ssDNA detection), Chk1 phosphorylation assay PloS one Medium 21998700
2018 PML acts as a reactive oxygen species (ROS) sensor. Pml−/− cells accumulate ROS, whereas PML expression decreases ROS levels. Pml−/− animals fail to properly activate oxidative stress-responsive p53 targets, while the NRF2 response is amplified. In an oxidative stress-prone background, Pml−/− animals display a longevity phenotype reflecting decreased basal p53 activation. PML couples ROS sensing to p53 responses through NB biogenesis. Pml−/− mouse models, ROS measurement assays, p53 target gene induction assays, acetaminophen hepatotoxicity model, fasting-induced steatosis model, glutathione depletion experiment The Journal of experimental medicine Medium 28931625
2019 PML RBCC domain undergoes sequential oligomerization (monomer → dimer → tetramer → N-mer) mediated by B1-box interfaces (W157, F158, SD1). Crystal structure of PML B1-box at 2.0 Å resolution and SAXS characterization define these interfaces. B1 interface mutations abolish PML SUMOylation and nuclear body biogenesis in HeLaPml−/− cells. In vivo, PML-RARα F158E mutation (disrupting B1 oligomerization) precludes leukemogenesis in transgenic mice. Crystal structure (2.0 Å), SAXS, gel filtration, ultracentrifugation, B1 interface mutagenesis, PML nuclear body reconstitution in HeLaPml−/− cells, transgenic mouse leukemogenesis model, single-cell RNA sequencing Nature communications High 31439836
2017 WDR4-containing CRL4WDR4 ubiquitin ligase mediates PML ubiquitination and degradation. This pathway is hyperactivated in lung cancer. The WDR4/PML axis induces CD73, uPAR, and SAA2 to elicit paracrine effects promoting migration, invasion, and metastasis. In vivo, this axis elevates intratumoral Tregs and M2-like macrophages and reduces CD8+ T cells. Co-immunoprecipitation, ubiquitination assays, WDR4 knockdown/overexpression, xenograft and genetically engineered mouse models, CD73 blockade rescue The Journal of clinical investigation Medium 28691927
2010 Overexpression of nuclear PML isoforms (I–VI) in human cells increases IFN-γ-induced STAT1 phosphorylation, enhances STAT1 DNA binding, activates IFN-stimulated genes, and increases their protein products. These effects require PML nuclear localization, PML SUMOylation, and the RING finger domain. Conversely, PML knockdown or PML−/− MEFs show decreased IFN-γ-induced STAT1 phosphorylation and STAT1 DNA-binding activity. PML isoform overexpression, PML siRNA knockdown, PML−/− MEF analysis, STAT1 phosphorylation assays, EMSA for STAT1 DNA binding, ISG expression assays, SUMOylation mutant analysis Biochimie Medium 21115099
2018 PML physically binds TET2 via its C-terminal domain and recruits TET2 to PML-positive nuclear bodies, promoting 5-hydroxymethylcytosine (5hmC) formation in response to chemotherapeutic agents. PML-RARA (missing the PML C-terminal domain) disrupts this interaction. Knockout of PML abolishes doxorubicin-promoted DNA modification. SILAC immunoprecipitation-mass spectrometry, co-immunoprecipitation, PML KO cells, 5hmC quantification, domain-deletion mutant analysis Cancer research Medium 29735542
2017 PML undergoes oxidation-mediated multimerization and de-SUMOylation in response to Listeria monocytogenes infection via the pore-forming toxin listeriolysin O (LLO). This de-SUMOylation is sensed as a danger signal leading to restriction of bacterial intracellular multiplication. Specific induction of PML de-SUMOylation phenocopies the LLO-induced antibacterial response. PML oxidation/multimerization assays, SUMOylation immunoblotting, LLO-deficient Listeria mutant comparison, PML de-SUMOylation induction, transcriptomic and proteomic microarrays, Pml−/− cell infection assays mBio Medium 28074026
2018 IFN-α treatment increases global cellular SUMOylation in a PML-dependent manner. This effect is orchestrated specifically by PML isoforms III and IV. IFN-α induces PML-dependent transfer of the SUMO E2 enzyme UBC9 to the nuclear matrix where it colocalizes with PML in nuclear bodies and enhances global SUMOylation. Large-scale SUMO proteomics (mass spectrometry), individual PML isoform expression in PML-negative cells, UBC9 nuclear matrix fractionation, immunofluorescence co-localization Molecular & cellular proteomics Medium 29535160
2011 PML physically interacts with TBX2 (a T-box transcription factor) and negatively regulates TBX2 expression. Recruitment of PML to the TBX2 promoter depends on a functional p130/E2F4 repressor complex, implementing transcriptionally inactive chromatin at the TBX2 promoter. TBX2 depletion triggers PML pro-senescence functions; elevated TBX2 antagonizes PML pro-senescence function through direct protein-protein interaction. ChIP, gene expression profiling, promoter reporter assay, co-immunoprecipitation, TBX2 knockdown and overexpression, senescence assays The EMBO journal Medium 22002537
1991 The MYL/PML-RARα fusion protein encoded by the t(15;17) translocation of APL includes RAR-α DNA- and retinoid-binding regions but lacks the RAR-α N-terminal A/B transactivation domain. The fusion protein acts as a retinoid-inducible transcription factor with ligand-independent repressor and ligand-dependent activator functions, and has ~10-fold greater affinity for RA than RARα alone. cDNA cloning and sequencing, retinoid-binding assays, transactivation reporter assays Oncogene Medium 1650447
1998 PML overexpression induces rapid cell death independent of de novo transcription, caspase-3 activation, or cell cycling. BAX and p27KIP1 are novel PML nuclear body-associated proteins recruited by PML. Arsenic enhances targeting of PML, BAX, and p27KIP1 to nuclear bodies and synergizes with PML and IFN to induce cell death. Caspase inhibitors (zVAD) accelerate PML-induced death. PML overexpression in multiple cell lines, immunofluorescence for BAX/p27KIP1 localization at NBs, caspase inhibitor treatment, arsenic trioxide treatment, cell death assays Nature genetics Medium 9806544
2022 PML/RARα is neddylated in its RARα moiety; this neddylation enhances DNA-binding ability of PML/RARα and impedes phase separation of the PML moiety, disrupting PML nuclear body assembly. Deneddylation of PML/RARα restores its phase separation to reconstruct functional PML nuclear bodies and activates RARα signaling, suppressing leukemogenesis. Pharmacological neddylation inhibition by MLN4924 eradicates APL cells in vitro and in vivo. Neddylation site identification, DNA-binding assays, phase separation assays, PML NB reconstitution, MLN4924 treatment in vitro and in APL mouse models Cell death and differentiation Medium 35194189
2008 UBE1L (ubiquitin-activating enzyme E1-like) induces ISG15 conjugation (ISG15ylation) of the PML domain of PML/RARα, causing its repression and degradation via the proteasome. This is mechanistically distinct from RA-induced RARα-domain targeting. USP18/UBP43 (the ISG15 deconjugase) opposes UBE1L-dependent (but not RA-dependent) PML/RARα degradation. Domain-specific transfection assays, ISG15ylation assays, proteasome inhibitor studies, USP18 rescue experiments Molecular cancer therapeutics Medium 18413804

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nature cell biology 611 18408733
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 459 20452955
2008 The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature 455 18716620
2002 The role of PML in tumor suppression. Cell 453 11832207
1998 Role of PML in cell growth and the retinoic acid pathway. Science (New York, N.Y.) 439 9488655
2000 The function of PML in p53-dependent apoptosis. Nature cell biology 396 11025664
2001 PML protein isoforms and the RBCC/TRIM motif. Oncogene 382 11704850
2007 PML and PML nuclear bodies: implications in antiviral defence. Biochimie 368 17343971
2004 PML nuclear bodies: dynamic sensors of DNA damage and cellular stress. BioEssays : news and reviews in molecular, cellular and developmental biology 334 15351967
1991 Structure and origin of the acute promyelocytic leukemia myl/RAR alpha cDNA and characterization of its retinoid-binding and transactivation properties. Oncogene 329 1650447
1998 PML induces a novel caspase-independent death process. Nature genetics 322 9806544
2006 PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature 320 16915281
2004 Cytoplasmic PML function in TGF-beta signalling. Nature 256 15356634
2000 Review: properties and assembly mechanisms of ND10, PML bodies, or PODs. Journal of structural biology 238 10806078
2000 Promyelocytic leukemia (PML) nuclear bodies are protein structures that do not accumulate RNA. The Journal of cell biology 223 10648561
2008 PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop. Molecular cell 221 19111660
2001 DNA viruses and viral proteins that interact with PML nuclear bodies. Oncogene 217 11704855
1995 Induction of the PML protein by interferons in normal and APL cells. Leukemia 196 8609713
2002 PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Nature cell biology 195 12402044
2018 PML nuclear bodies: from architecture to function. Current opinion in cell biology 185 29723661
1999 Cell cycle regulation of PML modification and ND10 composition. Journal of cell science 164 10574707
2003 Role of PML and the PML-nuclear body in the control of programmed cell death. Oncogene 148 14663483
2016 Emerging Role of PML Nuclear Bodies in Innate Immune Signaling. Journal of virology 144 27053550
2004 PML nuclear bodies and apoptosis. Oncogene 143 15077145
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 133 23734343
2011 Regulation of E2Fs and senescence by PML nuclear bodies. Genes & development 133 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
2001 PML interaction with p53 and its role in apoptosis and replicative senescence. Oncogene 103 11704853
2018 PML: Regulation and multifaceted function beyond tumor suppression. Cell & bioscience 94 29416846
2008 New insights into the role of PML in tumour suppression. Cell research 93 18504460
2003 Body language: the function of PML nuclear bodies in apoptosis regulation. Cell death and differentiation 93 12934066
2003 ZIP kinase triggers apoptosis from nuclear PML oncogenic domains. Molecular and cellular biology 88 12917339
2017 PML is a ROS sensor activating p53 upon oxidative stress. The Journal of experimental medicine 86 28931625
2010 PML isoforms I and II participate in PML-dependent restriction of HSV-1 replication. Journal of cell science 86 21172801
1992 Characterization of a fusion cDNA (RARA/myl) transcribed from the t(15;17) translocation breakpoint in acute promyelocytic leukemia. Molecular and cellular biology 86 1310153
2012 Update on PML and PML-IRIS occurring in multiple sclerosis patients treated with natalizumab. Journal of neuropathology and experimental neurology 84 22710964
2009 Therapy-induced PML/RARA proteolysis and acute promyelocytic leukemia cure. Clinical cancer research : an official journal of the American Association for Cancer Research 79 19808868
2014 PML nuclear bodies: assembly and oxidative stress-sensitive sumoylation. Nucleus (Austin, Tex.) 78 25482067
2017 The functional roles of PML nuclear bodies in genome maintenance. Mutation research 73 28521962
2008 PML activates transcription by protecting HIPK2 and p300 from SCFFbx3-mediated degradation. Molecular and cellular biology 73 18809579
2017 Ubiquitination of tumor suppressor PML regulates prometastatic and immunosuppressive tumor microenvironment. The Journal of clinical investigation 68 28691927
2008 Histone deacetylase 7 promotes PML sumoylation and is essential for PML nuclear body formation. Molecular and cellular biology 66 18625722
2003 Physical and functional interactions between PML and MDM2. The Journal of biological chemistry 64 12759344
2017 Manipulating PML SUMOylation via Silencing UBC9 and RNF4 Regulates Cardiac Fibrosis. Molecular therapy : the journal of the American Society of Gene Therapy 56 28143738
2010 SIRT1 stabilizes PML promoting its sumoylation. Cell death and differentiation 51 20577263
2016 Stratification and therapeutic potential of PML in metastatic breast cancer. Nature communications 50 27553708
2012 PML regulates PER2 nuclear localization and circadian function. The EMBO journal 50 22274616
2015 PML/TRIM19-Dependent Inhibition of Retroviral Reverse-Transcription by Daxx. PLoS pathogens 49 26566030
2000 The puzzling multiple lives of PML and its role in the genesis of cancer. BioEssays : news and reviews in molecular, cellular and developmental biology 49 10944585
2008 PML NBs (ND10) and Daxx: from nuclear structure to protein function. Frontiers in bioscience : a journal and virtual library 48 18508722
2009 PML nuclear bodies as sites of epigenetic regulation. Frontiers in bioscience (Landmark edition) 47 19273133
2020 PML Nuclear Body Biogenesis, Carcinogenesis, and Targeted Therapy. Trends in cancer 42 32527650
2008 UBE1L represses PML/RAR{alpha} by targeting the PML domain for ISG15ylation. Molecular cancer therapeutics 42 18413804
1996 PML, PLZF and NPM genes in the molecular pathogenesis of acute promyelocytic leukemia. Haematologica 41 8952164
2010 PML positively regulates interferon gamma signaling. Biochimie 39 21115099
2017 NPM1 Mutant Mediated PML Delocalization and Stabilization Enhances Autophagy and Cell Survival in Leukemic Cells. Theranostics 38 28740552
2013 PML, SUMOylation, and Senescence. Frontiers in oncology 38 23847762
2006 ATR, PML, and CHK2 play a role in arsenic trioxide-induced apoptosis. The Journal of biological chemistry 38 16891316
2000 Lack of expression for the suppressor PML in human small cell lung carcinoma. International journal of cancer 38 10699936
2007 Establishment and characterization of a novel imatinib-sensitive chronic myeloid leukemia cell line MYL, and an imatinib-resistant subline MYL-R showing overexpression of Lyn. European journal of haematology 37 17432977
2011 Functional connection between Rad51 and PML in homology-directed repair. PloS one 36 21998700
2015 PML-RARA requires DNA methyltransferase 3A to initiate acute promyelocytic leukemia. The Journal of clinical investigation 35 26595813
2011 PAX5-PML acts as a dual dominant-negative form of both PAX5 and PML. Oncogene 35 21217775
2007 Expression and localization of Werner syndrome protein is modulated by SIRT1 and PML. Mechanisms of ageing and development 34 17996922
2016 PML plays both inimical and beneficial roles in HSV-1 replication. Proceedings of the National Academy of Sciences of the United States of America 33 27162364
2014 Clearance of PML/RARA-bound promoters suffice to initiate APL differentiation. Blood 33 25258343
2011 The nuclear bodies inside out: PML conquers the cytoplasm. Current opinion in cell biology 33 21501958
2011 Physical and functional interaction between PML and TBX2 in the establishment of cellular senescence. The EMBO journal 33 22002537
2002 Opposing effects of PML and PML/RAR alpha on STAT3 activity. Blood 33 12506013
1996 The PML and PML/RARalpha domains: from autoimmunity to molecular oncology and from retinoic acid to arsenic. Experimental cell research 33 8986606
2019 B1 oligomerization regulates PML nuclear body biogenesis and leukemogenesis. Nature communications 32 31439836
2012 The role of PML ubiquitination in human malignancies. Journal of biomedical science 30 22935031
2014 PML control of cytokine signaling. Cytokine & growth factor reviews 29 24861946
1992 RARA and PML genes in acute promyelocytic leukemia. Leukemia & lymphoma 29 1337847
2018 PML Recruits TET2 to Regulate DNA Modification and Cell Proliferation in Response to Chemotherapeutic Agent. Cancer research 28 29735542
2009 PML links aberrant cytokine signaling and oncogenic stress to cellular senescence. Frontiers in bioscience (Landmark edition) 28 19273079
2000 The promyelocytic (PML) nuclear compartment and transcription control. Biochemical pharmacology 28 11007958
2018 Promyelocytic Leukemia Protein (PML) Requirement for Interferon-induced Global Cellular SUMOylation. Molecular & cellular proteomics : MCP 27 29535160
2017 The Human CMV IE1 Protein: An Offender of PML Nuclear Bodies. Advances in anatomy, embryology, and cell biology 27 28528440
2016 The interferon-induced antiviral protein PML (TRIM19) promotes the restriction and transcriptional silencing of lentiviruses in a context-specific, isoform-specific fashion. Retrovirology 27 27000403
2018 A pharmacokinetics phase 1 bioequivalence study of the trastuzumab biosimilar MYL-1401O vs. EU-trastuzumab and US-trastuzumab. British journal of clinical pharmacology 24 29926514
2022 Deneddylation of PML/RARα reconstructs functional PML nuclear bodies via orchestrating phase separation to eradicate APL. Cell death and differentiation 23 35194189
2013 PML-mediated signaling and its role in cancer stem cells. Oncogene 23 23563177
2006 A cytoplasmic PML mutant inhibits p53 function. Cell cycle (Georgetown, Tex.) 23 17172828
2014 The PML domain of PML-RARα blocks senescence to promote leukemia. Proceedings of the National Academy of Sciences of the United States of America 22 25092303
2022 Regulating the p53 Tumor Suppressor Network at PML Biomolecular Condensates. Cancers 21 36230470
2019 PML Bodies in Mitosis. Cells 21 31416160
2017 Tripartite Motif-Containing Protein 22 Interacts with Class II Transactivator and Orchestrates Its Recruitment in Nuclear Bodies Containing TRIM19/PML and Cyclin T1. Frontiers in immunology 21 28555140
2017 PML nuclear bodies contribute to the basal expression of the mTOR inhibitor DDIT4. Scientific reports 20 28332630
2011 Nogo-B regulates migration and contraction of airway smooth muscle cells by decreasing ARPC 2/3 and increasing MYL-9 expression. Respiratory research 20 21251247
1996 The biologic function of PML and its role in acute promyelocytic leukemia. Leukemia & lymphoma 20 9031108
2020 Role of PML SUMOylation in arsenic trioxide-induced fibrosis in HSCs. Life sciences 19 32240679
2018 PML/RARA inhibits expression of HSP90 and its target AKT. British journal of haematology 19 30536958
2017 Promyelocytic Leukemia Protein (PML) Controls Listeria monocytogenes Infection. mBio 19 28074026
2009 Perspectives in PML: a unifying framework for PML function. Frontiers in bioscience (Landmark edition) 19 19273081
2015 TRIM19/PML Restricts HIV Infection in a Cell Type-Dependent Manner. Viruses 18 26703718

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