Affinage

PARP4

Protein mono-ADP-ribosyltransferase PARP4 · UniProt Q9UKK3

Length
1724 aa
Mass
192.6 kDa
Annotated
2026-06-10
24 papers in source corpus 14 papers cited in narrative 14 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

PARP4 (VPARP/p193) is a mono(ADP-ribose) transferase that functions both as a structural and enzymatic component of the cytoplasmic vault ribonucleoprotein and as a free regulator of DNA-damage signaling and apoptosis (PMID:10477748, PMID:42054439). Within the vault, PARP4 docks onto MVP through its C-terminal region in an activity-independent manner, lines the inner surface of the assembled particle, and ADP-ribosylates MVP (PMID:10477748, PMID:15504404, PMID:15567158, PMID:40691181); its BRCT domain binds vault RNA through an electropositive surface, and PARP4 incorporation governs vault cargo selection and subcellular localization (PMID:37971310, PMID:40412520, PMID:40691181). Crystallographic analysis shows the catalytic active site is open to NAD+ but configured to deposit mono- rather than poly(ADP-ribose), with the BRCT and WGR domains tuning catalytic output (PMID:37971310). Outside the vault, PARP4 ADP-ribosylates PIDD1 at E783 downstream of an ATR-phosphorylation/PIAS1-SUMOylation cascade that licenses PARP4 docking, a mark required for caspase-2 dimerization and PIDDosome completion in response to DNA interstrand cross-links and reversed by the hydrolase PARP14 (PMID:42054439). PARP4 also mono-ADP-ribosylates Ku80 to support non-homologous end joining, such that its loss impairs double-strand break repair and confers synthetic lethality with ATM inhibition (PMID:39885134), and it interacts with hnRNPM to regulate intronic pre-mRNA splicing and restrain tumorigenicity independently of the vault (PMID:39034402). Consistent with a tumor-restraining and proapoptotic role, PARP4 normally limits cardiomyocyte cell cycle reentry (PMID:11375269, PMID:15142950) and its depletion enhances cancer cell proliferation and chemoresistance (PMID:26699384, PMID:37013346).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1999 High

    Established PARP4 as a bona fide ADP-ribosylating enzyme and a resident component of the vault particle, defining MVP as a substrate.

    Evidence Yeast two-hybrid, in vitro ADP-ribosylation with purified recombinant catalytic domain, and immunofluorescence

    PMID:10477748

    Open questions at the time
    • Did not resolve whether enzymatic activity is required for vault association
    • Functional consequence of MVP ADP-ribosylation unknown
  2. 2001 Medium

    Defined a proapoptotic, cell-cycle-restricting role for PARP4 in cardiomyocytes distinct from p53.

    Evidence Dominant-interfering p193 truncation mutants in ES-cell-derived cardiomyocytes with apoptosis and cell cycle readouts

    PMID:11375269

    Open questions at the time
    • Molecular mechanism of the proapoptotic activity not defined
    • Relies on truncation/dominant-interfering constructs rather than endogenous loss
  3. 2004 Medium

    Localized PARP4 structurally to the vault interior and showed it restricts cardiomyocyte cell cycle reentry in vivo after injury.

    Evidence CryoEM difference mapping of recombinant vaults; transgenic dominant-interfering p193 mouse with BrdU and histology post-infarction

    PMID:15142950 PMID:15504404

    Open questions at the time
    • CryoEM resolution did not give atomic contacts
    • In vivo phenotype based on dominant-interfering allele, not knockout
  4. 2005 Medium

    Showed PARP4 incorporation into vaults is rapid and stable and that its C-terminus, not its catalytic activity, mediates MVP binding.

    Evidence Pulse-chase immunoprecipitation and co-sedimentation of a C-terminal truncation with MVP particles in E. coli

    PMID:15567158

    Open questions at the time
    • Atomic-level interface not mapped
    • Single-lab biochemical reconstitution
  5. 2006 Medium

    Placed PARP4 in a complex with CUL7/Parc and p53, linking it to apoptotic regulation though distinct from its proapoptotic activity.

    Evidence Reciprocal Co-IP/Western and apoptosis assays in U2OS cells with dominant-interfering mutant

    PMID:17229476

    Open questions at the time
    • Apoptosis resistance shown to be independent of complex disruption, leaving mechanism unresolved
    • No reciprocal validation of direct PARP4-p53 contact
  6. 2015 Low

    Provided initial functional evidence for PARP4 as a tumor suppressor in breast cancer.

    Evidence siRNA knockdown and proliferation assay in HCC1143 cells

    PMID:26699384

    Open questions at the time
    • Single proliferation assay, single cell line, no pathway placement
    • No mechanism linking PARP4 enzymatic activity to growth restraint
  7. 2023 Medium

    Resolved the catalytic and BRCT architecture explaining why PARP4 is a mono-ART and how its domains regulate activity and bind vault RNA.

    Evidence X-ray crystallography of catalytic and BRCT-WGR-CAT constructs with in vitro activity and vault RNA-binding assays; bisulfite methylation profiling and rescue for promoter regulation

    PMID:37013346 PMID:37971310

    Open questions at the time
    • Vault RNA binding does not stimulate activity, so its functional role remains undefined
    • Physiological substrates beyond MVP not addressed structurally
  8. 2024 Medium

    Identified hnRNPM as a PARP4 partner and a vault-independent role in pre-mRNA splicing and tumor restraint.

    Evidence Quantitative MS interactomics, in vitro/in vivo tumorigenicity assays, and transcriptomic splicing analysis in cells and patient tumors

    PMID:39034402

    Open questions at the time
    • Whether ADP-ribosylation of hnRNPM mediates the splicing effect not shown
    • Single-lab interactomics
  9. 2025 High

    Delivered atomic-resolution definition of the PARP4-MVP/NAD+ vault interface, the BRCT-vault RNA contact, and a Ku80-dependent role in NHEJ.

    Evidence Cryo-EM of the vault cage with PARP4/NAD+ plus vault proteomics; BRCT crystal structure with mutagenesis; Ku80 ADP-ribosylation and DSB repair assays with ATM-inhibitor synthetic lethality

    PMID:39885134 PMID:40412520 PMID:40691181

    Open questions at the time
    • Function of interior vault NAD+-binding sites unresolved
    • Mechanism by which PARP4 selects vault cargo not defined
  10. 2026 High

    Defined a complete writer-eraser ADP-ribosylation switch controlling PIDDosome assembly and caspase-2 activation after interstrand cross-links.

    Evidence PIDD1 E783 ADP-ribosylation and site-specific mutagenesis, PARP4/PARP14 loss-of-function, caspase-2 dimerization and PIDDosome assays, epistasis with ATR and PIAS1

    PMID:42054439

    Open questions at the time
    • Whether vault-resident or free PARP4 performs this modification unclear
    • Generality beyond ICL-induced stress not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PARP4's vault-resident enzymatic activity, splicing role, and DNA-damage signaling functions are coordinated within a single cell remains unresolved.
  • No model integrating vault localization with substrate access to PIDD1/Ku80
  • Physiological role of vault RNA binding to the BRCT domain unknown
  • Catalytic versus scaffolding contributions to tumor suppression not separated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0003723 RNA binding 2
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 1
Pathway
R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2 R-HSA-8953854 Metabolism of RNA 1
Partners
CUL7HNRNPMKU80MVPP53PARP14PIDD1
Complex memberships
vault ribonucleoprotein particle

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 PARP4 (p193/VPARP) was identified as a poly(ADP-ribose) polymerase: its catalytic domain, expressed and purified from bacteria, catalyzes a poly(ADP-ribosylation) reaction in vitro. Purified vault particles retain this enzymatic activity, and MVP is a substrate for vault-associated PARP activity. A portion of p193 localizes to the nucleus and to the mitotic spindle. Yeast two-hybrid screen (identification of MVP interaction), peptide sequence analysis, in vitro poly(ADP-ribosylation) assay with purified recombinant catalytic domain, immunofluorescence and biochemical fractionation The Journal of cell biology High 10477748
2004 CryoEM difference mapping localized VPARP (PARP4) to three density bands lining the inner surface of the vault particle, establishing its structural position within the assembled vault ribonucleoprotein complex. Cryoelectron microscopy and single-particle image reconstruction with difference mapping of recombinant vaults co-expressing MVP and VPARP Journal of molecular biology High 15504404
2005 Newly synthesized VPARP is completely incorporated into vault particles within 1.5 hours and is stable once incorporated. The C-terminal region of VPARP lacking poly(ADP-ribose)polymerase activity is sufficient for co-sedimentation with MVP-assembled vault-like particles, indicating that PARP4 enzymatic activity is not required for its interaction with MVP. Immunoprecipitation pulse-chase assay, co-sedimentation of C-terminal VPARP truncation mutant with MVP particles in E. coli expression system Biochemical and biophysical research communications Medium 15567158
2001 p193 (PARP4) encodes a proapoptotic activity in cardiomyocytes: a C-terminal truncation mutant of p193 confers prosurvival activity, and combined expression of this mutant with a dominant-interfering p53 mutant blocks E1A-induced apoptosis in embryonic stem cell-derived cardiomyocytes, demonstrating that p193 and p53 define two distinct proapoptotic pathways that restrict cardiomyocyte cell cycle activity. Transgene expression of p193 truncation mutant in differentiating embryonic stem cell-derived cardiomyocytes; apoptosis assays combined with cell cycle analysis; structure-function analysis Circulation research Medium 11375269
2004 Expression of a dominant-interfering p193 (PARP4) mutant in transgenic cardiomyocytes induces cardiomyocyte cell cycle reentry at the infarct border zone after myocardial infarction and reduces hypertrophic growth in interventricular septa, indicating p193 normally restricts cardiomyocyte cell cycle activity in the injured adult heart. Transgenic mouse model expressing dominant-interfering p193 mutant under cardiac-specific promoter; BrdU incorporation assay; histological analysis post-coronary artery occlusion Circulation research Medium 15142950
2006 Endogenous p193/CUL7 (PARP4) forms a complex with Parc (a parkin-like ubiquitin ligase) and p53, as detected by immunoprecipitation/Western analysis. Expression of a dominant-interfering p193 truncation (1152stop) confers resistance to MG132- and etoposide-induced apoptosis, but this resistance is independent of disruption of the endogenous p193/CUL7–Parc–p53 complex. Immune precipitation/Western blot analysis; apoptosis assays in U2OS cells expressing dominant-interfering p193 mutant Biochimica et biophysica acta Medium 17229476
2015 siRNA knockdown of PARP4 in HCC1143 breast cancer cells significantly enhanced cell proliferation, suggesting PARP4 functions as a tumor suppressor in breast cancer cells. siRNA knockdown; cell proliferation assay Endocrine-related cancer Low 26699384
2023 X-ray crystal structures of the PARP4 catalytic domain reveal an active site open to NAD+ interaction (in contrast to the closed conformation of PARP1), and structures of the minimal ADP-ribosyltransferase fold show active site alterations that restrict PARP4 to mono(ADP-ribose) rather than poly(ADP-ribose) modifications. The BRCT-WGR-CAT construct has lower activity than the CAT domain alone, indicating the BRCT and WGR domains regulate catalytic output. PARP4 was also shown to interact with vault RNA, with the BRCT domain primarily responsible for this interaction, though vault RNA binding does not stimulate mono(ADP-ribosylation) activity. X-ray crystallography; in vitro ADP-ribosylation activity assays; RNA-binding assays with vault RNA Nucleic acids research High 37971310
2025 X-ray structure of the isolated PARP4 BRCT domain was determined, and structure-based mutagenesis identified four BRCT mutants that disrupt vault RNA interaction to varying degrees. An electropositive surface region of the BRCT domain mediates nucleic acid binding. The isolated BRCT domain is sufficient to mediate interaction with vault RNA. X-ray crystallography; structure-based mutagenesis; in vitro vault RNA-binding assays The Journal of biological chemistry High 40412520
2025 Cryo-EM structure of the human vault cage in complex with PARP4 and NAD+ revealed atomic-level details of the PARP4-MVP binding interface and unexpected NAD+-binding sites within the interior of the vault cage. Proteomics of vaults from wild-type vs. PARP4-depleted cells showed PARP4 incorporation regulates the subset of cargo proteins associated with the vault and its subcellular localization. Cryo-EM structure determination; proteomics of immunopurified vault particles from wild-type and PARP4-depleted cells Nature communications High 40691181
2024 PARP4 depletion or the I1039T mutation promotes tumorigenicity of KRAS- or EGFR-driven lung cancer cells independently of the vault complex. Quantitative mass spectrometry interactomics identified hnRNPM as a novel PARP4 interaction partner. Loss of hnRNPM similarly promotes tumor formation and results in dysregulated intronic splicing patterns that are also observed in PARP4 knockdown cells. In vitro and in vivo tumorigenicity assays; quantitative mass spectrometry interactomics; transcriptomic splicing analysis in cell lines and patient tumors Genome medicine Medium 39034402
2025 PARP4 catalyzes mono-ADP-ribosylation of Ku80 and thereby participates in non-homologous end joining (NHEJ) DNA double-strand break repair. PARP4 deficiency impairs DSB repair and sensitizes melanoma cells to ATM inhibitor in a synthetic lethal manner. PARP4 knockdown/knockout; DSB repair assays (NHEJ pathway markers); Ku80 mono-ADP-ribosylation assay; cell viability assays with ATM inhibitor Cell death discovery Medium 39885134
2026 PARP4 ADP-ribosylates PIDD1 at conserved E783 in the PIDD1 death domain (DD) in response to DNA interstrand cross-links (ICL). This modification is triggered downstream of ATR phosphorylation-induced, PIAS1-mediated SUMOylation of the PIDD1 DD, which enables PARP4 docking. E783 ADP-ribosylation is required for caspase-2 dimerization and PIDDosome completion, but not for RAIDD and caspase-2 recruitment. PARP14 (a ribosylhydrolase) reverses this modification. Loss of PARP4 eliminates caspase-2 activation and apoptosis in response to ICL. ADP-ribosylation assays with PIDD1 substrate; mutagenesis of E783; PARP4 and PARP14 knockdown/knockout; caspase-2 dimerization and PIDDosome assembly assays; genetic epistasis with ATR and PIAS1 Science advances High 42054439
2023 PARP4 expression is epigenetically regulated by promoter CpG methylation: hypomethylation of specific CpG sites (cg18582260 and cg17117459) in the PARP4 promoter correlates with upregulated PARP4 mRNA in cisplatin-resistant ovarian cancer cell lines. Treating cisplatin-sensitive cell lines with a demethylation agent restores PARP4 expression. Depletion of PARP4 in cisplatin-resistant cell lines reduced cisplatin chemoresistance and promoted cisplatin-induced DNA fragmentation. Bisulfite methylation analysis; demethylating agent treatment; siRNA knockdown; cell viability and DNA fragmentation assays BMB reports Medium 37013346

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The 193-kD vault protein, VPARP, is a novel poly(ADP-ribose) polymerase. The Journal of cell biology 340 10477748
2004 Cryoelectron microscopy imaging of recombinant and tissue derived vaults: localization of the MVP N termini and VPARP. Journal of molecular biology 75 15504404
2004 Cul7/p185/p193 binding to simian virus 40 large T antigen has a role in cellular transformation. Journal of virology 63 14990695
2004 Expression of mutant p193 and p53 permits cardiomyocyte cell cycle reentry after myocardial infarction in transgenic mice. Circulation research 51 15142950
2015 Germline PARP4 mutations in patients with primary thyroid and breast cancers. Endocrine-related cancer 50 26699384
2001 Coexpression of mutant p53 and p193 renders embryonic stem cell-derived cardiomyocytes responsive to the growth-promoting activities of adenoviral E1A. Circulation research 27 11375269
2005 Characterization of MVP and VPARP assembly into vault ribonucleoprotein complexes. Biochemical and biophysical research communications 24 15567158
2024 PARP4 interacts with hnRNPM to regulate splicing during lung cancer progression. Genome medicine 14 39034402
2019 Assessment of PARP4 as a candidate breast cancer susceptibility gene. Breast cancer research and treatment 13 31119570
2023 Identification of a novel PARP4 gene promoter CpG locus associated with cisplatin chemoresistance. BMB reports 12 37013346
2006 Expression of a mutant p193/CUL7 molecule confers resistance to MG132- and etoposide-induced apoptosis independent of p53 or Parc binding. Biochimica et biophysica acta 12 17229476
2023 Structural and biochemical analysis of the PARP1-homology region of PARP4/vault PARP. Nucleic acids research 11 37971310
2017 vPARP Adjusts MVP Expression in Drug-resistant Cell Lines in Conjunction with MDR Proteins. Anticancer research 11 28551640
2019 Genetic variants of PARP4 gene and PARP4P2 pseudogene in patients with multiple primary tumors including thyroid cancer. Mutation research 10 31203137
2004 Analysis of MVP and VPARP promoters indicates a role for chromatin remodeling in the regulation of MVP. Biochimica et biophysica acta 9 15093136
2009 Expression of a transgene encoding mutant p193/CUL7 preserves cardiac function and limits infarct expansion after myocardial infarction. Heart (British Cardiac Society) 7 19435717
2020 Modification of PARP4, XRCC3, and RAD51 Gene Polymorphisms on the Relation between Bisphenol A Exposure and Liver Abnormality. International journal of environmental research and public health 6 32316696
2025 Structural insights into the roles of PARP4 and NAD+ binding in the human vault cage. Nature communications 4 40691181
2025 PARP4 deficiency enhances sensitivity to ATM inhibitor by impairing DNA damage repair in melanoma. Cell death discovery 3 39885134
2022 Modification Effect of PARP4 and ERCC1 Gene Polymorphisms on the Relationship between Particulate Matter Exposure and Fasting Glucose Level. International journal of environmental research and public health 2 35627777
2025 Crystal structure and mutagenesis of a nucleic acid-binding BRCT domain in human PARP4. The Journal of biological chemistry 1 40412520
2024 Structural Insights into the Roles of PARP4 and NAD + in the Human Vault Cage. bioRxiv : the preprint server for biology 1 38979142
2026 PARP4 drives tumor progression by promoting glioma cell proliferation and invasion as a potential therapeutic target. Discover oncology 0 41999525
2026 PARP4 ADP-ribosylates PIDD1 to complete a phospho/SUMO/PAR-ylation cascade that orchestrates PIDDosome assembly. Science advances 0 42054439

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