Affinage

POLDIP2

Polymerase delta-interacting protein 2 · UniProt Q9Y2S7

Length
368 aa
Mass
42.0 kDa
Annotated
2026-06-10
48 papers in source corpus 28 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

POLDIP2 (PDIP38) is a compact two-domain adaptor protein—an N-terminal YccV-like SH3 β-barrel and a C-terminal DUF525 immunoglobulin-like β-sandwich (PMID:33884680)—that operates as a multifunctional scaffold across mitochondrial, redox, and DNA-transaction processes. In mitochondria, where it is imported to the matrix in a membrane-potential-dependent manner and associates with the mtDNA nucleoid (PMID:16428295, PMID:33159171), it controls oxidative metabolism by regulating the ClpP/CLPXP protease: its YccV domain docks CLPX while its DUF525 domain shapes substrate specificity and protects CLPX from LONM-mediated degradation (PMID:33159171). Through this protease axis POLDIP2 governs ClpP-dependent turnover of the lipoate-activating enzyme ACSM1 to maintain PDH and αKGDH lipoylation and mitochondrial respiration, with its loss stabilizing HIF-1α and reprogramming metabolism (PMID:29434038), and it acts as a heme-sensing adaptor that delivers heme-bound ALAS to CLPXP for negative-feedback degradation. As a redox regulator, POLDIP2 binds the NADPH oxidase subunit p22phox and Nox4, activating Nox4-derived H2O2 to drive RhoA/FAK-dependent focal adhesion maturation and vascular smooth muscle cell migration—including sulfenylation of F-actin at Cys272/Cys374 that promotes vinculin binding (PMID:19574552, PMID:25063792, PMID:30354218)—while conversely restraining Nox2 by sequestering p47phox (PMID:36828293). In DNA metabolism, POLDIP2 binds the p50 subunit of DNA polymerase δ and PCNA (PMID:12522211) and directly stimulates the polymerase activity and processivity of PrimPol via an arginine cluster in its DUF525 domain, promoting error-free 8-oxoG bypass and supporting replication fork progression in the same epistasis group as PrimPol (PMID:26984527, PMID:33533925); it also engages translesion polymerases (Polη, Rev1, Polζ) and shifts DNA damage tolerance from template switching toward translesion synthesis (PMID:20554254, PMID:30840704). POLDIP2 additionally localizes to the mitotic spindle and is required for proper chromosome segregation (PMID:18843206). In vivo, endothelial, myeloid, and vascular POLDIP2 promote inflammatory adhesion, barrier disruption, and fibrotic signaling through RhoA, FAK/Pyk2-integrin, NF-κB, and TGF-β1/SMAD3 pathways (PMID:31779628, PMID:34528082, PMID:35535614, PMID:38968428).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2003 High

    Established POLDIP2's first molecular partners, linking it to the replication/repair machinery before any pathway context existed.

    Evidence Yeast two-hybrid plus orthogonal biochemistry (GST pulldown, PCNA overlay, CoIP) identifying binding to DNA pol δ p50 and PCNA

    PMID:12522211

    Open questions at the time
    • No functional consequence of the interaction defined
    • No structural basis for binding established at this stage
  2. 2005 High

    Resolved where POLDIP2 acts by showing it is predominantly a mitochondrial matrix nucleoid protein, reframing it beyond a nuclear polymerase factor.

    Evidence Subcellular fractionation, proteinase K protection, CoIP and crosslinking to TFAM, mtSSB, HSP60 and a Lon homolog in HeLa cells

    PMID:16428295

    Open questions at the time
    • Functional role at the nucleoid not defined
    • Relationship between mitochondrial and nuclear pools unresolved
  3. 2008 Medium

    Added a mitotic function, showing POLDIP2 is required for spindle integrity and chromosome segregation.

    Evidence Immunofluorescence/live imaging plus antibody microinjection and siRNA loss-of-function in mammalian cells

    PMID:18843206

    Open questions at the time
    • Molecular partners at the spindle unidentified
    • Mechanism connecting spindle role to other functions unknown
  4. 2009 High

    Defined POLDIP2 as a positive regulator of Nox4-derived ROS driving cytoskeletal/focal adhesion remodeling, opening its redox-signaling role.

    Evidence Y2H, reciprocal CoIP with p22phox/Nox4, NADPH oxidase activity and ROS assays, RhoA activation, dominant-negative RhoA rescue in VSMCs

    PMID:19574552

    Open questions at the time
    • Molecular target of H2O2 in the cytoskeleton not yet identified
    • Link to mitochondrial functions unaddressed
  5. 2010 Medium

    Connected POLDIP2 to translesion synthesis by mapping direct interactions with TLS polymerases and a UV-survival phenotype.

    Evidence Direct interaction assays (Polη UBZ domain, Rev1, Polζ via Rev7), siRNA knockdown, Polη foci imaging, UV survival in human cells

    PMID:20554254

    Open questions at the time
    • Directionality of TLS regulation not quantified
    • In vitro reconstitution of polymerase stimulation absent
  6. 2014 High

    Established mechanistic epistasis placing POLDIP2 upstream of Nox4/RhoA/FAK in focal adhesion turnover and migration, and embedded it in a RhoA/ROCK feedback loop.

    Evidence Adenoviral overexpression, siRNA, live focal-adhesion imaging, traction force microscopy, RhoA/FAK rescue in VSMCs; RhoA/ROCK inhibition in kidney myofibroblasts

    PMID:24872317 PMID:25063792

    Open questions at the time
    • Direct oxidative substrate still not identified at this stage
    • Generalizability beyond vascular/fibroblast cells unclear
  7. 2014 Medium

    Linked POLDIP2 loss to a cell-cycle/proliferation phenotype, implicating E2F-driven Cdk1/CyclinA2 and p21 control.

    Evidence Gene-trap knockout MEFs, flow cytometry, Western blotting, SV40 large T-antigen rescue

    PMID:24797518

    Open questions at the time
    • Mechanism connecting POLDIP2 to E2F/p21 not defined
    • p21 increase not explained by the SV40-rescuable pathway
  8. 2016 High

    Demonstrated direct enzymatic stimulation of PrimPol by POLDIP2, defining a concrete replication-fork function and shared epistasis group.

    Evidence Interaction mapping to PrimPol catalytic domain, in vitro polymerase/processivity and 8-oxoG bypass assays, DNA fiber assays, epistasis with PrimPol-/-

    PMID:26984527

    Open questions at the time
    • Residue-level basis of stimulation not yet mapped
    • Contribution of mitochondrial vs nuclear pool unresolved
  9. 2018 High

    Defined POLDIP2's mitochondrial metabolic role through ClpP-dependent ACSM1 turnover controlling lipoylation, respiration, and HIF-1α stability.

    Evidence Knockout/knockdown, metabolic flux, lipoylation assays, Seahorse respiration, HIF-1α stabilization, protease analysis, rescue

    PMID:29434038

    Open questions at the time
    • Direct biochemical link between POLDIP2 and ClpP activity not yet structurally defined
    • Cancer relevance correlative
  10. 2018 High

    Identified the molecular target of Nox4-derived H2O2 as F-actin, showing site-specific cysteine sulfenylation promotes vinculin binding and migration.

    Evidence siRNA/overexpression, DCP-Bio1 sulfenylation assay, CoIP, actin C272A/C374A point mutants, adhesion/migration assays

    PMID:30354218

    Open questions at the time
    • Spatial coupling of Nox4 to actin not structurally resolved
    • Whether mitochondrial POLDIP2 contributes to this pool unaddressed
  11. 2018 Medium

    Extended the proliferation phenotype to vascular pathology, placing p21 downstream of POLDIP2 in VSMC proliferation and neointima formation.

    Evidence siRNA in rat aortic SMCs, proliferation/PCNA assays, p21 siRNA rescue, mouse femoral artery wire-injury model

    PMID:30237457

    Open questions at the time
    • Mechanism of p21 regulation by POLDIP2 unknown
    • Relationship to redox vs metabolic functions unclear
  12. 2019 High

    Defined the directionality of POLDIP2 in DNA damage tolerance, showing it biases the balance from template switching toward translesion synthesis.

    Evidence Gene disruption in DT40 and TK6, Ig V gene conversion/hypermutation analysis, sister chromatid exchange, UV/H2O2 sensitivity assays

    PMID:30840704

    Open questions at the time
    • Substrate selectivity among TLS polymerases not quantified
    • No structural basis for TS-vs-TLS choice
  13. 2019 High

    Expanded POLDIP2 into vascular phenotype control and inflammation, connecting it to O-GlcNAcylation/SRF/KLF4 and NF-κB/Cox-2 pathways.

    Evidence In vivo/in vitro knockout, RNA-seq, UPS activity and OGT inhibition assays (VSMC differentiation); Poldip2+/- mice, p65 translocation and Cox-2 epistasis (BBB)

    PMID:31656131 PMID:31779628

    Open questions at the time
    • Direct molecular target linking POLDIP2 to OGT/UPS not identified
    • How a single adaptor coordinates these divergent pathways unresolved
  14. 2020 High

    Provided the structural and biochemical basis for mitochondrial adaptor function, showing domain-specific CLPX docking and protection from LONM degradation.

    Evidence Crystal structure, reconstitution, domain interaction mapping, import assay, CLPXP substrate-specificity and LONM degradation assays

    PMID:33159171

    Open questions at the time
    • Full set of CLPXP substrates POLDIP2 selects not enumerated
    • Regulation of POLDIP2 import in vivo unaddressed
  15. 2021 High

    Delivered the full POLDIP2 structure and identified the DUF525 arginine cluster as the determinant of PrimPol stimulation.

    Evidence X-ray crystallography, CD, SAXS, MD simulation; in vitro polymerase and dNTP/DNA binding assays with arginine-cluster mutagenesis

    PMID:33533925 PMID:33884680

    Open questions at the time
    • Role of the dynamic N-terminus in partner selection not fully defined
    • How one fold supports both mitochondrial and replication functions unresolved
  16. 2021 Medium

    Probed a direct POLDIP2–Tau interaction, with conflicting cellular versus in vitro effects on Tau aggregation.

    Evidence In vitro ThT kinetics, dot-blot, AFM (inhibits aggregation); earlier cell/Drosophila screen mapping pro-aggregation to DUF525

    PMID:25930997 PMID:34071254

    Open questions at the time
    • In vitro and cellular outcomes are opposite and unreconciled
    • Physiological relevance to neurodegeneration uncertain
  17. 2022 High

    Established cell-type-specific in vivo roles in inflammation, dissecting endothelial RhoA/permeability and myeloid integrin/Pyk2 contributions.

    Evidence Endothelial-specific KO (sepsis lung injury, RhoA/VE-cadherin); myeloid-specific KO (β2-integrin activation, Pyk2); hypoxia/CDK2/EZH2 repression of POLDIP2

    PMID:34528082 PMID:35535614 PMID:36596387

    Open questions at the time
    • Whether redox vs scaffolding activity drives each phenotype unresolved
    • Upstream signals selecting which pathway POLDIP2 engages unclear
  18. 2023 Medium

    Distinguished POLDIP2's opposing NADPH oxidase regulation, showing direct p47phox sequestration suppresses Nox2 assembly.

    Evidence In vitro NADPH oxidase assays with fractionated neutrophil membranes and recombinant POLDIP2, protein interaction assays

    PMID:36828293

    Open questions at the time
    • Structural basis of p47phox sequestration not defined
    • In vivo relevance of Nox2 suppression not established
  19. 2024 High

    Defined POLDIP2 as a heme-sensing adaptor coupling ALAS turnover to CLPXP, integrating its protease-adaptor role with heme homeostasis.

    Evidence Biochemical reconstitution, pulldown of heme-bound ALAS, ALAS turnover in POLDIP2-KO cells, domain deletion (preprint)

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Disease relevance to X-linked protoporphyria correlative
  20. 2025 Medium

    Showed a conserved in vivo mitochondrial function for the POLDIP2–ClpX axis in paternal mtDNA elimination during spermatogenesis.

    Evidence Forward genetic screen, genetic disruption, imaging, ChIP and CoIP in Drosophila

    PMID:39934413

    Open questions at the time
    • Mechanism of mtDNA-targeted elimination not defined
    • Conservation in mammalian spermatogenesis untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how a single small two-domain adaptor mechanistically partitions among its mitochondrial protease, NADPH oxidase redox, replication/TLS polymerase, and spindle roles, and what regulates its distribution between organelles.
  • No unified model of pool partitioning between mitochondria and nucleus
  • No structure of POLDIP2 bound to its replication or oxidase partners
  • Regulation of context-specific function selection unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 3 GO:0003677 DNA binding 2 GO:0140098 catalytic activity, acting on RNA 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005739 mitochondrion 4 GO:0005634 nucleus 2 GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-69306 DNA Replication 3 R-HSA-1430728 Metabolism 2 R-HSA-73894 DNA Repair 2 R-HSA-1640170 Cell Cycle 1
Partners
CLPXNOX4P22PHOXP47PHOXPCNAPRIMPOLSMAD3TFAM
Complex memberships
CLPXP proteaseNADPH oxidase (Nox4/p22phox)mtDNA nucleoid

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 PDIP38 (POLDIP2) was identified as a binding partner of the p50 subunit of DNA polymerase delta and of PCNA, confirmed by GST pulldown assays, PCNA overlay experiments, co-immunoprecipitation from calf thymus and mammalian cell extracts, immunoaffinity chromatography, and native gel electrophoresis. Yeast two-hybrid, GST pulldown, PCNA overlay, co-immunoprecipitation, immunoaffinity chromatography, native gel electrophoresis The Journal of biological chemistry High 12522211
2005 PDIP38 localizes predominantly to the mitochondrial matrix (not nuclear) in HeLa cells, where it co-immunoprecipitates with mitochondrial transcription factor A (TFAM) and mitochondrial single-stranded DNA binding protein (mtSSB), and crosslinks to mtSSB, the 60 kDa heat shock protein, and a Lon protease homolog, indicating association with the mitochondrial DNA nucleoid. Subcellular fractionation, proteinase K protection assay, co-immunoprecipitation, formaldehyde crosslinking Journal of biochemistry High 16428295
2008 PDIP38 localizes to the mitotic spindle throughout mitosis, and its loss-of-function (antibody injection or siRNA silencing) causes spindle organization defects, aberrant chromosome segregation, and multinucleated cells. Immunofluorescence/live imaging, antibody microinjection, siRNA knockdown, cell biology assays Cell cycle (Georgetown, Tex.) Medium 18843206
2009 Poldip2 associates with p22phox, Nox1, and Nox4, colocalizes with p22phox at sites of Nox4 localization, and increases Nox4 enzymatic activity ~3-fold, thereby positively regulating basal ROS production (superoxide and H2O2) in vascular smooth muscle cells. Poldip2 overexpression activates RhoA, strengthens focal adhesions, and increases stress fiber formation; these effects are blocked by dominant-negative RhoA. Depletion of Poldip2 or Nox4 causes loss of these structures, rescued by active RhoA. Yeast two-hybrid, co-immunoprecipitation, colocalization, NADPH oxidase activity assay, ROS measurement, RhoA activation assay, dominant-negative rescue, siRNA knockdown, overexpression Circulation research High 19574552
2010 PDIP38 directly interacts with TLS polymerase Polη via Polη's UBZ domain, and also interacts with Rev1 and Polζ (via Rev7). Depletion of PDIP38 increases Polη foci in undamaged cells and reduces cell survival after UV irradiation. Direct protein interaction assays, co-immunoprecipitation, siRNA knockdown, immunofluorescence, UV survival assay DNA repair Medium 20554254
2013 In response to UV irradiation (or transcriptional stress), PDIP38 is translocated to nuclear speckles/spliceosomes, and its depletion (shRNA) greatly reduces UV-induced alternative splicing of MDM2 transcripts. Immunofluorescence with nuclear subcompartment markers, shRNA knockdown, nested RT-PCR for alternative splicing Cell cycle (Georgetown, Tex.) Medium 23989611
2014 Poldip2 regulates focal adhesion turnover and VSMC migration via Nox4/RhoA/FAK-dependent signaling: overexpression blocks focal adhesion dissolution and sustains H2O2 in focal adhesions; Nox4 silencing prevents focal adhesion stabilization by Poldip2; RhoA inhibition blocks Poldip2-mediated attenuation of focal adhesion dissolution; overexpression of RhoA or FAK reverses the loss of focal adhesions induced by Poldip2 knockdown. Adenoviral overexpression, siRNA knockdown, live imaging of focal adhesion dynamics, RhoA activity assay, H2O2 measurement in focal adhesions, traction force microscopy American journal of physiology. Heart and circulatory physiology High 25063792
2014 In kidney myofibroblasts, RhoA/ROCK signaling acts upstream of Poldip2-dependent Nox4 regulation and ROS production during TGF-β1-induced myofibroblast activation; inhibition of RhoA (siRNA) or ROCK (Y-27632) significantly reduced Poldip2 and Nox4 protein and NADPH oxidase activity. siRNA knockdown, pharmacological inhibition (Y-27632), NADPH oxidase activity assay, Western blotting American journal of physiology. Renal physiology Medium 24872317
2014 Poldip2 knockout mouse embryonic fibroblasts display reduced proliferation (not due to apoptosis or senescence), increased autophagy (elevated LC3b), G1/G2M arrest with reduced S-phase cells, increased p53 S20 phosphorylation and Sirt1, downregulation of Cdk1 and CyclinA2, and increased p21CIP1; the Cdk1/CyclinA2 changes are reversed by SV40 large T-antigen (implicating E2F pathway), while p21 increase is not. Gene-trap mouse model, flow cytometry, Western blotting, population doubling, SV40 large T-antigen rescue experiment PloS one Medium 24797518
2015 POLDIP2 promotes Tau aggregation through impairment of autophagy (and partially proteasome) activity; this activity resides in the DUF525 domain. Knockdown of Drosophila POLDIP2 homolog CG12162 attenuated Tau overexpression-induced neurodegeneration and extended lifespan of Tau(R406W) transgenic flies. cDNA expression library cell-based screen, ectopic overexpression/knockdown, Tau aggregation assay, autophagy/proteasome activity assay, domain deletion analysis, Drosophila genetic model Biochemical and biophysical research communications Medium 25930997
2016 PolDIP2 directly interacts with PrimPol's catalytic domain, stimulates PrimPol's polymerase activity and processivity, enhances dNTP/DNA binding, and promotes error-free bypass of 8-oxoG lesions. PolDIP2 depletion in human cells reduces replication fork rates similarly to PrimPol-/- cells; PolDIP2 depletion in PrimPol-/- cells causes no further decrease, placing them in the same epistasis group. Protein interaction mapping, in vitro polymerase assay, processivity assay, 8-oxoG bypass assay, DNA fiber assay (replication fork rates), siRNA knockdown, epistasis analysis Nucleic acids research High 26984527
2018 Poldip2 is a nuclear-encoded mitochondrial protein that controls lipoylation of pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (αKGDH) complexes by regulating the ClpP protease complex and degradation of the lipoate-activating enzyme ACSM1. Poldip2 deficiency reduces lipoylation, represses mitochondrial respiration, stabilizes HIF-1α (via loss of substrate inhibition of PHDs), and induces metabolic reprogramming resembling hypoxia/cancer adaptation. Poldip2 expression is repressed by hypoxia and basally suppressed in triple-negative cancer cells. Genetic knockout/knockdown, metabolic flux analysis, lipoylation assays, mitochondrial respiration (Seahorse), HIF-1α stabilization assay, protease complex analysis, overexpression rescue Proceedings of the National Academy of Sciences of the United States of America High 29434038
2018 Poldip2/NOX4 activates NOX4 during integrin-mediated cell adhesion, leading to H2O2-mediated sulfenylation of filamentous actin (F-actin) at Cys272 and Cys374; oxidized F-actin promotes its binding to vinculin, facilitating focal adhesion maturation and cell migration. Depletion of Poldip2 or NOX4, or scavenging H2O2, inhibits F-actin oxidation; actin point mutants (C272A/C374A) that resist oxidation impair vinculin binding and migration. SiRNA knockdown, overexpression, H2O2 measurement, sulfenylation assay (DCP-Bio1), co-immunoprecipitation, point mutagenesis of actin, cell adhesion/migration assays Arteriosclerosis, thrombosis, and vascular biology High 30354218
2018 Poldip2 knockdown in rat aortic smooth muscle cells reduces serum-induced proliferation and PCNA expression, and upregulates p21. siRNA-mediated downregulation of p21 rescues the proliferation inhibition caused by Poldip2 knockdown, placing p21 downstream of Poldip2 in VSMC proliferation control. siRNA knockdown, cell proliferation assay, Western blotting, epistasis by p21 siRNA rescue, neointima formation in mouse femoral artery wire injury model Laboratory investigation Medium 30237457
2019 Poldip2 mediates LPS-induced blood-brain barrier disruption by regulating NF-κB subunit p65 nuclear translocation and downstream Cox-2/prostaglandin E2 induction in brain endothelial cells; heterozygous deletion of Poldip2 protects against BBB permeability, and Cox-2 inhibition (meloxicam) reverses BBB disruption in WT but not Poldip2+/- mice. Poldip2+/- mouse model, Evans blue permeability assay, immunoblotting, ELISA, siRNA knockdown in brain endothelial cells, immunofluorescence of p65 translocation, FITC-dextran transwell assay Journal of neuroinflammation High 31779628
2019 Poldip2 deficiency induces a highly differentiated VSMC phenotype through upregulation of the hexosamine biosynthetic pathway and OGT-mediated protein O-GlcNAcylation, which inhibits a nuclear ubiquitin proteasome system responsible for SRF stabilization and KLF4 repression; Poldip2-deficient VSMCs resist dedifferentiation and macrophage-like conversion in response to cholesterol or PDGF. Genetic knockdown/knockout (in vitro and in vivo mouse aorta), RNA-seq, Western blotting, UPS activity assays, OGT inhibition, cholesterol/PDGF challenge Circulation research High 31656131
2019 PDIP38 shifts DNA damage tolerance in mammalian and chicken cells from template switching (TS) toward translesion synthesis (TLS): PDIP38-/- cells show increased immunoglobulin gene conversion (TS) and reduced non-templated hypermutation (TLS) in DT40, and increased sister chromatid exchanges in both DT40 and human TK6 cells, without increased sensitivity to UV or H2O2. Gene disruption (CRISPR/gene targeting) in DT40 and TK6, Ig V gene sequence analysis, sister chromatid exchange assay, UV/H2O2 sensitivity assay PloS one High 30840704
2020 Human PDIP38 is directed to the mitochondrial matrix in a membrane-potential-dependent manner. Its N-terminal YccV-like domain (SH3-like β-barrel) interacts specifically with CLPX via CLPX's N-terminal zinc-binding domain adaptor docking loop. Its C-terminal DUF525 domain forms an immunoglobulin-like β-sandwich with a conserved substrate-binding pocket. PDIP38 modulates CLPX substrate specificity and protects CLPX from LONM-mediated degradation, stabilizing cellular CLPX levels. Crystal structure, biochemical reconstitution, domain interaction mapping, mitochondrial import assay (membrane potential dependence), CLPXP substrate specificity assay, LONM degradation assay Communications biology High 33159171
2021 Crystal structure of POLDIP2 to 2.8 Å reveals a compact two-domain β-strand-rich globular fold comprising YccV (SH3-like β-barrel) and DUF525 (immunoglobulin-like β-sandwich) domains with a conserved central channel containing a modified cysteine residue; molecular dynamics reveals a highly dynamic N-terminal region tethered by an extended linker, which likely mediates interactions with binding partners including PrimPol and PCNA. X-ray crystallography, circular dichroism, SAXS, molecular dynamics simulation, ab initio modelling Protein science High 33884680
2021 PolDIP2 uses a flexible loop to interact with the C-terminal ApaG-like (DUF525) domain of PolDIP2 on PrimPol's catalytic domain; a unique arginine cluster in PolDIP2 is required for increasing PrimPol's primer-template and dNTP binding affinities, thereby enhancing nucleotide incorporation efficiency and processivity. In vitro polymerase assay, dNTP/DNA binding affinity measurements, mutagenesis of PolDIP2 arginine cluster, protein interaction mapping Nucleic acids research High 33533925
2021 PolDIP2 directly interacts with Tau protein in vitro and inhibits Tau oligomer formation and amyloid fibril growth, as shown by thioflavin-T kinetic assays, Tau oligomer dot-blot, and atomic force microscopy single-molecule analysis. Thioflavin-T aggregation kinetics, Tau oligomer dot-blot, atomic force microscopy, direct protein interaction assay International journal of molecular sciences Medium 34071254
2021 Poldip2 promotes VCAM-1 induction in brain endothelial cells following ischemia via activation of focal adhesion kinase (FAK); FAK activation was identified as a critical intermediary in Poldip2-mediated VCAM-1 induction, and Poldip2 depletion in vivo attenuated myeloid cell infiltration and adhesion molecule induction after cerebral ischemia. Poldip2+/- mouse cerebral ischemia model, flow cytometry, RT-PCR, siRNA knockdown in brain endothelial cells, FAK activation assay, Western blotting Scientific reports Medium 33692398
2022 Endothelial Poldip2 regulates sepsis-induced lung injury via RhoA pathway activation: endothelial-specific Poldip2 knockout reduces LPS-induced lung leukocyte infiltration, inflammatory gene expression, and VCAM1 induction; in vitro, Poldip2 knockdown reduces TNFα-induced endothelial permeability, VE-cadherin disruption, and RhoA activation, with redistribution of active RhoA away from cell edges. Endothelial-specific conditional knockout mouse, BAL/lung tissue analysis, qPCR, siRNA knockdown in human pulmonary endothelial cells, transendothelial resistance assay, VE-cadherin immunofluorescence, RhoA activity assay Cardiovascular research High 34528082
2022 Poldip2 is repressed under hypoxia by a mechanism requiring activation of the EZH2 repressive complex downstream of CDK2; Poldip2 repression is required for CCN2/CTGF expression via metabolic inhibition of the ubiquitin-proteasome system leading to SRF stabilization; pharmacological or genetic CDK2 inhibition reverses Poldip2 downregulation, UPS inhibition, and fibrotic gene expression. Hypoxia exposure, CDK2 inhibition (pharmacological and siRNA), EZH2 inhibition, UPS activity assay, Western blotting, gene expression analysis Free radical biology & medicine Medium 36596387
2022 Myeloid Poldip2 is required for β2-integrin activation and Pyk2 phosphorylation in neutrophils, facilitating neutrophil adhesion to activated endothelium and transmigration; myeloid-specific Poldip2 knockout reduces LPS-induced lung leukocyte infiltration without affecting neutrophil surface β2-integrin expression, ROS production, NET formation, or cytokine induction. Myeloid-specific Poldip2 knockout mouse, BAL cell counts, β2-integrin activation assay, Pyk2 phosphorylation, neutrophil adhesion/transmigration assay, ROS assay, NET formation assay Journal of the American Heart Association Medium 35535614
2023 Poldip2 negatively modulates NADPH oxidase 2 (Nox2) activity in neutrophil membranes (~2.5-fold downregulation) by interacting with the regulatory subunit p47phox (not p22phox), trapping p47phox and preventing Nox2 assembly; this is opposite to its positive regulation of Nox4. In vitro NADPH oxidase activity assay with fractionated neutrophil membranes, recombinant purified Poldip2, protein interaction assays Free radical biology & medicine Medium 36828293
2024 POLDIP2 serves as a heme-sensing adaptor protein for the mitochondrial protease CLPXP: it directly recognizes heme-bound ALAS and drives assembly of the ALAS-CLPXP degradation complex for heme-induced negative feedback degradation of ALAS; loss of POLDIP2 strongly impairs ALAS turnover in cells. The C-terminal element of ALAS (truncated in X-linked dominant protoporphyria) is dispensable for POLDIP2 interaction but required for CLPXP-mediated degradation. Biochemical reconstitution, pulldown with heme-bound ALAS, ALAS turnover assay in cells (POLDIP2 knockout), domain deletion analysis bioRxivpreprint High
2025 In Drosophila spermatogenesis, Poldip2 is a mitochondrial matrix protein that binds mtDNA and is required for paternal mtDNA elimination; disruption of poldip2 causes substantial mtDNA retention in mature sperm and paternal mtDNA transmission. ClpX (key CLPXP component) interacts with Poldip2 and co-regulates mtDNA elimination in spermatids. Forward genetic screen, genetic disruption, imaging, biochemical analyses, ChIP assay, co-immunoprecipitation The EMBO journal Medium 39934413
2024 Poldip2 promotes SMAD3 activation and facilitates its nuclear translocation by directly interacting with SMAD3, enhancing expression of fibrosis markers (MMP9, COL-1, FN, CTGF) via TGF-β1/SMAD3 signaling in retinal pigment epithelial cells exposed to high glucose. siRNA/shRNA knockdown (in vitro and in vivo AAV9), co-immunoprecipitation (Poldip2-SMAD3 interaction), Western blotting, immunofluorescence of SMAD3 nuclear translocation Diabetes Medium 38968428

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circulation research 363 19574552
2014 RhoA/Rho kinase mediates TGF-β1-induced kidney myofibroblast activation through Poldip2/Nox4-derived reactive oxygen species. American journal of physiology. Renal physiology 106 24872317
2003 Identification of a novel protein, PDIP38, that interacts with the p50 subunit of DNA polymerase delta and proliferating cell nuclear antigen. The Journal of biological chemistry 99 12522211
2019 Poldip2 mediates blood-brain barrier disruption in a model of sepsis-associated encephalopathy. Journal of neuroinflammation 91 31779628
2022 Capsaicin ameliorates diabetic retinopathy by inhibiting poldip2-induced oxidative stress. Redox biology 74 36088760
2005 PDIP38 associates with proteins constituting the mitochondrial DNA nucleoid. Journal of biochemistry 66 16428295
2018 Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer. Proceedings of the National Academy of Sciences of the United States of America 56 29434038
2014 Poldip2 controls vascular smooth muscle cell migration by regulating focal adhesion turnover and force polarization. American journal of physiology. Heart and circulatory physiology 54 25063792
2016 PolDIP2 interacts with human PrimPol and enhances its DNA polymerase activities. Nucleic acids research 49 26984527
2010 Crosstalk between replicative and translesional DNA polymerases: PDIP38 interacts directly with Poleta. DNA repair 46 20554254
2014 Poldip2 knockout results in perinatal lethality, reduced cellular growth and increased autophagy of mouse embryonic fibroblasts. PloS one 39 24797518
2019 Mitochondrial Protein Poldip2 (Polymerase Delta Interacting Protein 2) Controls Vascular Smooth Muscle Differentiated Phenotype by O-Linked GlcNAc (N-Acetylglucosamine) Transferase-Dependent Inhibition of a Ubiquitin Proteasome System. Circulation research 35 31656131
2010 Complex sense-antisense architecture of TNFAIP1/POLDIP2 on 17q11.2 represents a novel transcriptional structural-functional gene module involved in breast cancer progression. BMC genomics 34 20158880
2013 PDIP38 is translocated to the spliceosomes/nuclear speckles in response to UV-induced DNA damage and is required for UV-induced alternative splicing of MDM2. Cell cycle (Georgetown, Tex.) 28 23989611
2018 NOX4 (NADPH Oxidase 4) and Poldip2 (Polymerase δ-Interacting Protein 2) Induce Filamentous Actin Oxidation and Promote Its Interaction With Vinculin During Integrin-Mediated Cell Adhesion. Arteriosclerosis, thrombosis, and vascular biology 25 30354218
2019 Poldip2 deficiency protects against lung edema and vascular inflammation in a model of acute respiratory distress syndrome. Clinical science (London, England : 1979) 22 30622219
2015 Essential role of POLDIP2 in Tau aggregation and neurotoxicity via autophagy/proteasome inhibition. Biochemical and biophysical research communications 21 25930997
2008 PDIP38 is a novel mitotic spindle-associated protein that affects spindle organization and chromosome segregation. Cell cycle (Georgetown, Tex.) 21 18843206
2022 Endothelial Poldip2 regulates sepsis-induced lung injury via Rho pathway activation. Cardiovascular research 20 34528082
2020 Poldip2 mediates blood-brain barrier disruption and cerebral edema by inducing AQP4 polarity loss in mouse bacterial meningitis model. CNS neuroscience & therapeutics 19 32790044
2019 PDIP38/PolDIP2 controls the DNA damage tolerance pathways by increasing the relative usage of translesion DNA synthesis over template switching. PloS one 19 30840704
2021 Poldip2 controls leukocyte infiltration into the ischemic brain by regulating focal adhesion kinase-mediated VCAM-1 induction. Scientific reports 18 33692398
2020 Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP. Communications biology 16 33159171
2019 Matrine pre-treatment suppresses AGEs- induced HCSMCs fibrotic responses by regulating Poldip2/mTOR pathway. European journal of pharmacology 13 31634459
2018 Poldip2 knockdown inhibits vascular smooth muscle proliferation and neointima formation by regulating the expression of PCNA and p21. Laboratory investigation; a journal of technical methods and pathology 13 30237457
2023 Nanoscale coordination polymer Fe-DMY downregulating Poldip2-Nox4-H2O2 pathway and alleviating diabetic retinopathy. Journal of pharmaceutical analysis 12 38174114
2022 Poldip2/Nox4 Mediates Lipopolysaccharide-Induced Oxidative Stress and Inflammation in Human Lung Epithelial Cells. Mediators of inflammation 12 35140544
2021 A unique arginine cluster in PolDIP2 enhances nucleotide binding and DNA synthesis by PrimPol. Nucleic acids research 11 33533925
2018 Case Report: Exome sequencing reveals recurrent RETSAT mutations and a loss-of-function POLDIP2 mutation in a rare undifferentiated tongue sarcoma. F1000Research 10 29862022
2018 Knockdown of POLDIP2 suppresses tumor growth and invasion capacity and is linked to unfavorable transformation ability and metastatic feature in non-small cell lung cancer. Experimental cell research 9 29684384
2022 MicroRNA 148a Suppresses Tuberculous Fibrosis by Targeting NOX4 and POLDIP2. International journal of molecular sciences 8 35328424
2019 Hepatic deficiency of Poldip2 in type 2 diabetes dampens lipid and glucose homeostasis. Metabolism: clinical and experimental 8 31351995
2025 Poldip2 promotes mtDNA elimination during Drosophila spermatogenesis to ensure maternal inheritance. The EMBO journal 7 39934413
2021 MIR31HG regulates the proliferation, migration and invasion of breast cancer by regulating the expression of POLDIP2. Journal of B.U.ON. : official journal of the Balkan Union of Oncology 7 34076993
2020 A Multifunctional Protein PolDIP2 in DNA Translesion Synthesis. Advances in experimental medicine and biology 7 32383114
2021 Crystal structure and molecular dynamics of human POLDIP2, a multifaceted adaptor protein in metabolism and genome stability. Protein science : a publication of the Protein Society 6 33884680
2022 Myeloid Poldip2 Contributes to the Development of Pulmonary Inflammation by Regulating Neutrophil Adhesion in a Murine Model of Acute Respiratory Distress Syndrome. Journal of the American Heart Association 5 35535614
2022 ZEB1 regulates bone metabolism in osteoporotic rats through inducing POLDIP2 transcription. Journal of orthopaedic surgery and research 5 36123704
2022 Metabolic regulation of the proteasome under hypoxia by Poldip2 controls fibrotic signaling in vascular smooth muscle cells. Free radical biology & medicine 5 36596387
2021 Characterization of Poldip2 knockout mice: Avoiding incorrect gene targeting. PloS one 5 34928942
2017 FGF Suppresses Poldip2 Expression in Osteoblasts. Journal of cellular biochemistry 5 27918072
2024 Overexpressed Poldip2 Incurs Retinal Fibrosis via the TGF-β1/SMAD3 Signaling Pathway in Diabetic Retinopathy. Diabetes 4 38968428
2021 Human Polymerase δ-Interacting Protein 2 (PolDIP2) Inhibits the Formation of Human Tau Oligomers and Fibrils. International journal of molecular sciences 4 34071254
2025 Poldip2 Aggravates inflammation in diabetic retinopathy by impairing mitophagy via the AMPK/ULK1/Pink1 pathway. Life sciences 3 40320136
2023 New insights in the molecular regulation of the NADPH oxidase 2 activity: Negative modulation by Poldip2. Free radical biology & medicine 3 36828293
2022 Poldip2 knockdown protects against lipopolysaccharide-induced acute lung injury via Nox4/Nrf2/NF-κB signaling pathway. Frontiers in pharmacology 3 36120334
2023 Knockout of AMD-associated gene POLDIP2 reduces mitochondrial superoxide in human retinal pigment epithelial cells. Aging 2 36795578
2026 Poldip2 deficiency attenuates lung disease severity in a mouse model of COVID-19. PloS one 0 42054341

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