Affinage

PDRG1

p53 and DNA damage-regulated protein 1 · UniProt Q9NUG6

Length
133 aa
Mass
15.5 kDa
Annotated
2026-06-10
14 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDRG1 is a small protein with dual roles in chromatin/epigenetic regulation and oncogenic signaling, acting both as a subunit of the prefoldin-like complex and as a modulator of DNA and histone methylation (PMID:40026265, PMID:27548429, PMID:41943853). As a structural component, PDRG1 associates principally with the prefoldin-like complex subunits UXT and URI, with an overlapping interactome that includes nuclear RNA polymerase subunits and spliceosome components, and its loss is developmentally lethal (PMID:40026265). PDRG1 lowers genomic methylation by physically binding MATα1, the catalytic subunit of methionine adenosyltransferases MAT I/III, reducing S-adenosylmethionine availability and DNA methylation (PMID:27548429). In parallel, PDRG1 directly binds EZH2 through its N-terminal residues 36–70, increasing H3K27me3 deposition at the CDKN1A (p21) promoter to repress p21 transcription and enable bypass of cellular senescence; restoring p21 reverses the growth arrest caused by PDRG1 loss (PMID:41943853). PDRG1 is transcriptionally activated by SP1 binding at its promoter (PMID:42243436) and is held downstream of a HIF1α–miR-519d regulatory axis (PMID:28057028). Through these activities PDRG1 functions as an oncogenic driver: it suppresses ATM/p53 signaling to promote radioresistance and survival (PMID:27610824, PMID:31383535) and activates MEK/ERK/CD44 and Wnt/β-catenin signaling to drive proliferation and migration across multiple cancer contexts (PMID:34812552, PMID:42243436).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2016 High

    The first molecular function for PDRG1 was established by showing it binds the MAT catalytic subunit and lowers DNA methylation, linking the protein to methionine/SAM metabolism.

    Evidence Yeast two-hybrid, reciprocal Co-IP, pull-down, and DNA methylation assays identifying MATα1 interaction

    PMID:27548429

    Open questions at the time
    • Does not establish how the interaction inhibits MAT enzymatic activity mechanistically
    • Nuclear versus cytoplasmic partitioning of the effect not fully resolved
  2. 2016 Medium

    PDRG1 was placed as a determinant of radioresistance by showing gain/loss of function alters survival through the ATM-p53 axis, beginning its characterization as a stress-response modulator.

    Evidence Gain- and loss-of-function transfection with viability, apoptosis assays and Western blot in lung cancer cells

    PMID:27610824

    Open questions at the time
    • No direct biochemical interaction with ATM demonstrated
    • Mechanism by which PDRG1 modulates ATM activity unknown
  3. 2017 Medium

    Upstream regulation of PDRG1 was clarified by positioning it downstream of a HIF1α–miR-519d axis controlling radiosensitivity.

    Evidence ChIP and luciferase reporter assays confirming HIF1α binding to miR-519d promoter and miR-519d targeting of PDRG1 mRNA in nasopharyngeal carcinoma

    PMID:28057028

    Open questions at the time
    • Does not address how PDRG1 protein level changes translate to downstream effectors
    • Generality of the axis beyond nasopharyngeal carcinoma untested
  4. 2019 Medium

    Pharmacological epistasis confirmed PDRG1 as an upstream suppressor of ATM/p53 signaling, consolidating its anti-apoptotic role.

    Evidence siRNA knockdown with ATM inhibitor (KU55933) rescue, flow cytometry, Western blot, and xenografts in gastric cancer

    PMID:31383535

    Open questions at the time
    • Direct molecular link between PDRG1 and ATM still missing
    • Whether the MAT/SAM or EZH2 activities feed into ATM suppression not tested
  5. 2019 Low

    PDRG1 was linked to Wnt signaling and chemosensitivity, expanding its oncogenic pathway repertoire.

    Evidence shRNA knockdown and overexpression with Western blot of β-catenin/cyclinD1 and cisplatin sensitivity assays in esophageal cancer

    PMID:31882431

    Open questions at the time
    • Pathway inference rests on protein expression changes without direct interaction evidence
    • No epistasis or rescue experiment to establish causality
  6. 2021 Medium

    Transcriptomic and in vivo work placed PDRG1 upstream of MEK/ERK/CD44 signaling driving glioblastoma proliferation and migration.

    Evidence shRNA knockdown, transcriptome sequencing, Western blot, migration/proliferation assays, and xenografts

    PMID:34812552

    Open questions at the time
    • No direct biochemical interaction with MEK/ERK components shown
    • Mechanism connecting PDRG1 to CD44 induction unresolved
  7. 2025 Medium

    The core structural identity of PDRG1 was defined as a prefoldin-like complex subunit, providing a conserved framework for its nuclear functions.

    Evidence In vivo AP-MS interactome mapping and genetic loss-of-function (embryonic lethal) in Arabidopsis showing UXT/URI as main interactors with RNA Pol and spliceosome overlap

    PMID:40026265

    Open questions at the time
    • Plant ortholog context limits direct translation to human PDRG1
    • How PFDLc membership relates to the MAT and EZH2 activities not integrated
  8. 2026 High

    A direct epigenetic mechanism was established: PDRG1 binds EZH2 via defined N-terminal residues to drive H3K27me3-mediated p21 repression and senescence bypass.

    Evidence Co-IP, ChIP-qPCR, RNA-seq, domain-mapping mutagenesis, p21 rescue, and xenografts

    PMID:41943853

    Open questions at the time
    • Whether EZH2 binding cooperates with the DNA methylation effect via MAT not tested
    • Structural basis of the residue 36–70 interaction not resolved
  9. 2026 Medium

    SP1 was identified as a direct transcriptional activator of PDRG1, and PDRG1 was confirmed to act through Wnt/β-catenin in hepatocellular carcinoma, completing an upstream-to-downstream signaling loop.

    Evidence ChIP/promoter binding, Western blot of Wnt effectors, XAV939 inhibitor rescue, and KD/OE in vitro and in vivo

    PMID:42243436

    Open questions at the time
    • Direct PDRG1–Wnt component interaction not demonstrated
    • Whether SP1 induction operates across other PDRG1-driven cancers untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PDRG1's prefoldin-like complex membership mechanistically unifies its distinct roles in DNA methylation, H3K27me3 deposition, and multiple oncogenic signaling pathways remains unresolved.
  • No structural model of human PDRG1 in complex with EZH2, MATα1, or PFDLc partners
  • Direct biochemical links to ATM, MEK/ERK, and Wnt components are absent
  • Integration of metabolic (SAM) and chromatin activities into a single pathway is undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0005198 structural molecule activity 1 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 2 R-HSA-4839726 Chromatin organization 1
Partners
EZH2MAT1ASP1URIUXT
Complex memberships
prefoldin-like complex (PFDLc)

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 PDRG1 physically interacts with MATα1 (the catalytic subunit of methionine adenosyltransferases MAT I and MAT III), as demonstrated by yeast two-hybrid, immunoprecipitation, and pull-down assays. Nuclear MATα1-PDRG1 interaction results in reduced DNA methylation levels, identifying downregulation of S-adenosylmethionine synthesis as the first functional effect directly ascribed to PDRG1. Yeast two-hybrid, co-immunoprecipitation, pull-down assays, DNA methylation assays PloS one High 27548429
2016 PDRG1 promotes radioresistance in lung cancer cells via the ATM-p53 signaling pathway, as shown by gain- and loss-of-function experiments affecting cell viability, apoptosis, and protein expression. Gain-of-function and loss-of-function transfection, cell viability assays, apoptosis assays, Western blot Biomedicine & pharmacotherapy Medium 27610824
2017 HIF1α directly targets the miR-519d promoter (chromatin immunoprecipitation and luciferase reporter assay), and miR-519d directly targets PDRG1 mRNA (luciferase reporter assay), placing PDRG1 downstream of a HIF1α-miR-519d axis in nasopharyngeal carcinoma radiosensitivity. Chromatin immunoprecipitation, luciferase reporter assay, stable overexpression/knockdown Journal of experimental & clinical cancer research Medium 28057028
2019 PDRG1 silencing in gastric cancer cells activates the ATM/p53 pathway (increased p-ATM, p53, p21, p-cdc2, cleaved caspase-3), arrests the cell cycle at G2/M, and induces apoptosis; pharmacological ATM inhibition (KU55933) reverses these effects, establishing PDRG1 as an upstream suppressor of ATM/p53 signaling. siRNA knockdown, Western blot, flow cytometry, ATM inhibitor rescue, xenograft model Pathology, research and practice Medium 31383535
2019 PDRG1 knockdown in esophageal cancer cells suppresses the Wnt signaling pathway, as evidenced by reduced cyclinD1 and β-catenin expression, increased apoptosis, and enhanced cisplatin sensitivity. shRNA knockdown, overexpression, Western blot, cell viability and apoptosis assays Annals of clinical and laboratory science Low 31882431
2021 PDRG1 promotes proliferation and migration of GBM cells via the MEK/ERK/CD44 pathway; PDRG1 knockdown reduces CD44 expression and transcriptome analysis confirmed enrichment of adhesion and motility gene sets. shRNA knockdown, transcriptome sequencing, Western blot, in vitro migration/proliferation assays, in vivo xenograft Cancer science Medium 34812552
2025 In Arabidopsis, PDRG1 functions primarily as a subunit of the prefoldin-like complex (PFDLc); in vivo interactome (AP-MS) shows PFDLc subunits (UXT, URI) are its main interactors with overlapping interactomes including nuclear RNA polymerase subunits and spliceosome components. PDRG1 impairment causes embryonic lethality, equivalent to loss of other PFDLc subunits. In vivo co-immunoprecipitation/AP-MS, genetic loss-of-function (embryonic lethal phenotype), interactome comparison FEBS letters Medium 40026265
2026 PDRG1 directly interacts with EZH2 (co-immunoprecipitation), and this interaction increases H3K27me3 enrichment at the p21 (CDKN1A) promoter (ChIP-qPCR), suppressing p21 transcription and allowing bypass of cellular senescence. Domain mapping identified PDRG1 N-terminal residues 36–70 as required for EZH2 binding. Restoration of p21 rescues the anti-proliferative phenotype caused by PDRG1 knockdown. Co-immunoprecipitation, ChIP-qPCR, RNA-seq, domain-mapping mutagenesis, rescue experiments, xenograft model International journal of biological sciences High 41943853
2026 Transcription factor SP1 directly binds the PDRG1 promoter at the E3 site (−1927 to −1917) and activates PDRG1 transcription; SP1-driven pro-tumor effects are rescued by PDRG1 silencing. PDRG1 in turn activates Wnt/β-catenin signaling (elevated β-catenin, c-Myc, phospho-GSK-3β), and Wnt inhibitor XAV939 reverses PDRG1 oncogenic effects in HCC. ChIP, luciferase reporter assay (implied by promoter binding), Western blot, Wnt pathway inhibitor rescue, KD/OE in vitro and in vivo MedScience Medium 42243436

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Oleuropein enhances radiation sensitivity of nasopharyngeal carcinoma by downregulating PDRG1 through HIF1α-repressed microRNA-519d. Journal of experimental & clinical cancer research : CR 36 28057028
2016 The Oncogene PDRG1 Is an Interaction Target of Methionine Adenosyltransferases. PloS one 18 27548429
2020 Long non-coding RNA LINC01419 mediates miR-519a-3p/PDRG1 axis to promote cell progression in osteosarcoma. Cancer cell international 14 32390762
2020 lncRNA FOXD2-AS1 promotes hemangioma progression through the miR-324-3p/PDRG1 pathway. Cancer cell international 14 32489325
2021 PDRG1 promotes the proliferation and migration of GBM cells by the MEK/ERK/CD44 pathway. Cancer science 13 34812552
2016 The PDRG1 is an oncogene in lung cancer cells, promoting radioresistance via the ATM-P53 signaling pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 12 27610824
2019 PDRG1 gene silencing contributes to inhibit the growth and induce apoptosis of gastric cancer cells. Pathology, research and practice 11 31383535
2017 PDRG1 at the interface between intermediary metabolism and oncogenesis. World journal of biological chemistry 9 29225734
2018 The Potential Roles of the Apoptosis-Related Protein PDRG1 in Diapause Embryo Restarting of Artemia sinica. International journal of molecular sciences 7 29301330
2019 Knockdown of PDRG1 Could Inhibit the Wnt Signaling Pathway in Esophageal Cancer Cells. Annals of clinical and laboratory science 3 31882431
2017 Molecular cloning, characterization and expression analysis of a novel PDRG1 gene from black tiger shrimp (Penaeus monodon). Genetics and molecular biology 2 28257526
2025 PDRG1 is essential for early plant development as a component of the prefoldin-like complex. FEBS letters 1 40026265
2026 Identification of a Novel PDRG1-EZH2-p21 Pathway Controlling Senescence and Tumor Progression in Hepatocellular Carcinoma. International journal of biological sciences 0 41943853
2026 PDRG1 induced by SP1 facilitates the proliferation and metastasis of hepatocellular carcinoma by activating the Wnt/β-catenin pathway. MedScience 0 42243436

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