POLDIP2 (Polymerase Delta-Interacting Protein 2): A Comprehensive Functional Review

Introduction

Polymerase delta-interacting protein 2 (POLDIP2), also known as PDIP38 (polymerase delta-interacting protein of 38 kDa), is a multifunctional adaptor protein that has emerged as a central nexus connecting genome stability, redox metabolism, and mitochondrial function in metazoan cells. Originally identified in 2003 through a yeast two-hybrid screen as an interacting partner of the p50 subunit of DNA polymerase delta and proliferating cell nuclear antigen (PCNA)[liu-2003-pdip38-discovery-abstract], the biological roles of POLDIP2 have expanded dramatically over the subsequent two decades. The protein has since been implicated in DNA damage tolerance through translesion synthesis, regulation of NADPH oxidase activity and reactive oxygen species production, mitochondrial protein quality control, metabolic adaptation to hypoxia, and regulation of the cytoskeleton[hernandes-2017-review-fulltext]. This review synthesizes current understanding of POLDIP2 molecular function, subcellular localization, pathway involvement, and physiological significance based on the primary scientific literature.

POLDIP2 is encoded by a gene on human chromosome 17q11.2 and is highly conserved throughout metazoans, though notably absent in prokaryotes, plants, and fungi[hernandes-2017-review-fulltext]. The conservation pattern suggests that POLDIP2 evolved through fusion of ancestral bacterial genes during the opisthokont radiation, likely after the Ichthyosporea split from the lineage leading to metazoans[kulik-2021-structure-abstract]. The essential nature of this protein is underscored by the observation that homozygous deletion in mice results in perinatal lethality, with only 3% of expected knockout animals surviving to birth[amanso-2014-knockout-abstract].

Protein Structure and Domain Architecture

POLDIP2 is translated as a 368-amino acid, 42 kDa protein that can be post-translationally processed to a 37 kDa form through cleavage of an N-terminal mitochondrial targeting sequence[hernandes-2017-review-fulltext]. The mature protein comprises two conserved globular domains connected by an alpha-helical linker region: an N-terminal YccV-like domain and a C-terminal DUF525 (Domain of Unknown Function 525) domain[kulik-2021-structure-abstract][strack-2020-clpxp-abstract].

The crystal structure of human POLDIP2 (residues 51-368) was determined at 2.8 Angstrom resolution and deposited in the Protein Data Bank (PDB: 6Z9C)[kulik-2021-structure-abstract]. This structure reveals a compact, beta-strand-rich globular architecture with the two domains positioned in close proximity through the conserved interdomain linker. The N-terminal (YccV-like) domain (residues 67-200) adopts an SH3-like beta-barrel fold, while the C-terminal (DUF525) domain (residues 233-368) forms an immunoglobulin-like beta-sandwich structure[kulik-2021-structure-abstract][strack-2020-clpxp-abstract].

A notable structural feature is an internal cavity or channel traversing the protein at the interface between the extended YccV and DUF525 domains. This channel is approximately 6.5 Angstroms wide and is lined with predominantly hydrophilic residues[kulik-2021-structure-abstract]. Within this channel, cysteine 266 displays anomalous electron density suggestive of an oxidized or otherwise modified state, raising the possibility that POLDIP2 may function as a redox sensor capable of conformational switching in response to the cellular oxidative environment[kulik-2021-structure-abstract]. Molecular dynamics simulations reveal that the N-terminal region preceding the YccV domain is highly dynamic, providing conformational flexibility that likely facilitates interactions with the protein's many diverse binding partners[kulik-2021-structure-abstract].

The YccV-like domain contains three potential PCNA-interacting protein (PIP) box motifs, with one (PIP2) located on a flexible loop and therefore accessible for PCNA binding[kulik-2021-structure-abstract]. The evolutionary origin of this domain traces to bacterial YccV (HspQ) proteins that bind hemimethylated DNA and regulate gene expression. The DUF525 domain shares homology with bacterial ApaG proteins and contains conserved motifs found in NAD- and FAD-binding proteins involved in binding the ADP moiety[liu-2003-pdip38-discovery-abstract][hernandes-2017-review-fulltext]. The C-terminal DUF525 domain harbors a highly conserved putative substrate binding pocket that is implicated in recognizing target proteins for delivery to the CLPXP protease[strack-2020-clpxp-abstract].

Subcellular Localization

POLDIP2 exhibits complex and cell-type-dependent subcellular localization patterns that reflect its multifunctional nature. The protein has been identified in the nucleus, mitochondrial matrix, cytoplasm, and plasma membrane, with distribution influenced by cell proliferation state and interactions with cell adhesion receptors[hernandes-2017-review-fulltext].

In vascular smooth muscle cells, POLDIP2 localizes prominently to focal adhesions and stress fibers, consistent with its roles in regulating cytoskeletal dynamics and NADPH oxidase 4 (Nox4) activity at these sites[lyle-2009-nox4-abstract]. Cell fractionation experiments across multiple cell types consistently demonstrate that the majority of POLDIP2 distributes to the mitochondrial fraction, with only a minor proportion detected in the nucleus[hernandes-2017-review-fulltext]. However, in certain cell types including rat bladder carcinoma NBT-II cells, intestinal epithelial IEC18 cells, rat brain endothelial cells, and HeLa cells, POLDIP2 does not localize to mitochondria[hernandes-2017-review-fulltext], highlighting the context-dependent nature of its distribution.

Mitochondrial targeting of POLDIP2 occurs in a membrane potential-dependent manner, and within mitochondria the protein resides in the matrix compartment where it colocalizes with its partner protein CLPX[strack-2020-clpxp-abstract]. The full-length 42 kDa form contains the mitochondrial targeting sequence, while cleavage of this sequence during or after mitochondrial import yields the 37 kDa form. Whether these two forms have distinct functional roles remains an important unresolved question[hernandes-2017-review-fulltext]. Notably, the N-terminal region required for interaction with PrimPol overlaps with the mitochondrial targeting sequence, and truncated POLDIP2 lacking the first 50 amino acids fails to stimulate PrimPol DNA polymerase activity, suggesting that the mitochondrial form may not regulate PrimPol function[guilliam-2016-primpol-abstract].

DNA Replication and Damage Tolerance Functions

Interaction with DNA Polymerase Delta and PCNA

POLDIP2 was originally identified through its physical association with the p50 subunit of DNA polymerase delta (encoded by POLD2), one of the core subunits of the replicative DNA polymerase[liu-2003-pdip38-discovery-abstract]. The interaction was demonstrated through multiple biochemical approaches including yeast two-hybrid analysis, GST pull-down assays, coimmunoprecipitation from calf thymus tissue and mammalian cell extracts, immunoaffinity chromatography, and native gel electrophoresis[liu-2003-pdip38-discovery-abstract]. POLDIP2 also directly interacts with PCNA, the DNA sliding clamp that serves as an essential processivity factor for DNA polymerase delta, suggesting that POLDIP2 may function as an integral component of the DNA replication machinery[liu-2003-pdip38-discovery-abstract][hernandes-2017-review-fulltext].

Biochemical studies demonstrate that POLDIP2 stimulates the DNA polymerase activity of Pol delta without affecting its fidelity[maga-2013-pol-lambda-abstract]. This enhancement of polymerase activity, combined with simultaneous interactions with PCNA and specialized translesion synthesis polymerases, positions POLDIP2 as a coordinator of polymerase switching events at sites of DNA damage.

Translesion Synthesis and DNA Damage Tolerance

One of the most well-characterized molecular functions of POLDIP2 is its role in DNA damage tolerance through regulation of translesion synthesis (TLS). When replicative DNA polymerases encounter lesions in template DNA strands, cells employ two principal strategies to restore stalled replication forks: error-prone translesion DNA synthesis by specialized DNA polymerases, and error-free template switching involving homologous recombination with the sister chromatid[tissier-2019-tls-vs-ts-abstract].

POLDIP2 physically associates with multiple TLS polymerases including DNA polymerase eta (Pol eta), DNA polymerase lambda (Pol lambda), DNA polymerase zeta (Pol zeta), Rev1, and the primase-polymerase PrimPol[hernandes-2017-review-fulltext][guilliam-2016-primpol-abstract][maga-2013-pol-lambda-abstract]. Yeast two-hybrid experiments confirmed direct interactions between POLDIP2 and Pol eta, Pol zeta, and Rev1[tissier-2019-tls-vs-ts-abstract]. Purified POLDIP2 stimulates TLS activity of Pol lambda and PrimPol in vitro through enhancement of DNA binding, processivity, and catalytic efficiency[maga-2013-pol-lambda-abstract][guilliam-2016-primpol-abstract].

The interaction between POLDIP2 and PrimPol has been particularly well characterized. PrimPol is a specialized enzyme possessing both primase and DNA polymerase activities involved in DNA damage tolerance and mitochondrial DNA maintenance[guilliam-2016-primpol-abstract]. POLDIP2 increases PrimPol's polymerase activity in a dose-dependent manner by enhancing DNA binding affinity and processivity[guilliam-2016-primpol-abstract]. Processivity measurements show that POLDIP2 extends PrimPol products from approximately 4 nucleotides to over 16 nucleotides per binding event, representing greater than a 4-fold improvement[guilliam-2016-primpol-abstract]. Cross-linking mass spectrometry revealed that POLDIP2's N-terminus (residues 1-8) mediates interaction with PrimPol's catalytic domain around amino acid positions 60-70, a region showing strong homology to Pol eta's POLDIP2-binding region[guilliam-2016-primpol-abstract]. Importantly, POLDIP2 also acts as a fidelity factor for PrimPol during bypass of 8-oxoguanine (8-oxoG) lesions, enhancing error-free dCTP incorporation opposite this common oxidative DNA lesion[guilliam-2016-primpol-abstract].

For DNA polymerase lambda, POLDIP2 similarly functions as a processivity factor specifically during 8-oxoG bypass[maga-2013-pol-lambda-abstract]. The physical interaction between POLDIP2 and Pol lambda increases both processivity and catalytic efficiency of error-free lesion bypass. POLDIP2 additionally stimulates Pol lambda and Pol eta-mediated bypass of other common DNA lesions including abasic sites and cyclobutane thymine dimers[maga-2013-pol-lambda-abstract]. Notably, POLDIP2 does not stimulate DNA polymerases beta or iota, indicating specificity in its regulatory effects[maga-2013-pol-lambda-abstract].

Cellular evidence supports the physiological importance of these biochemical activities. Depletion of POLDIP2 in human cells causes decreased replication fork rates following UV irradiation, similar to the phenotype observed in PrimPol-knockout cells[guilliam-2016-primpol-abstract]. Critically, depleting POLDIP2 in PrimPol-knockout cells does not produce a further decrease in fork rates, demonstrating that these proteins function epistatically in the same pathway[guilliam-2016-primpol-abstract]. POLDIP2 silencing also increases cellular sensitivity to oxidative stress, an effect potentiated in a Pol lambda-deficient background[maga-2013-pol-lambda-abstract].

Regulation of TLS versus Template Switching

Beyond activating individual TLS polymerases, POLDIP2 plays a broader regulatory role in determining the balance between translesion synthesis and template switching pathways. Studies in chicken DT40 B lymphocytes and human cell lines demonstrate that PDIP38/POLDIP2 shifts the DNA damage tolerance pathway balance toward TLS and away from template switching[tissier-2019-tls-vs-ts-abstract].

Disruption of PDIP38 in DT40 cells caused a three-fold decrease in TLS-mediated immunoglobulin V gene hypermutation while simultaneously increasing template switching frequency through immunoglobulin gene conversion[tissier-2019-tls-vs-ts-abstract]. Sister chromatid exchange analysis revealed that loss of PDIP38 increased UV-induced SCE by more than 50% in both chicken and human cell lines, indicating enhanced reliance on homologous recombination-based mechanisms[tissier-2019-tls-vs-ts-abstract]. Using a transposon-based assay system with integrated UV damage, researchers found that PDIP38-deficient cells showed a significant increase in the relative usage of template switching, from approximately 5% to 13-26%[tissier-2019-tls-vs-ts-abstract].

Rather than simply activating TLS polymerases, POLDIP2 appears to suppress template switching pathways, thereby increasing the relative contribution of translesion synthesis to overall damage tolerance without necessarily enhancing total cellular resistance to DNA-damaging agents[tissier-2019-tls-vs-ts-abstract]. This regulatory function may explain why both excessive and insufficient POLDIP2 levels can be detrimental to cells[hernandes-2017-review-fulltext].

NADPH Oxidase Regulation and Redox Signaling

Discovery as a Nox4 Activator

A major functional role for POLDIP2 outside of DNA metabolism was discovered through a yeast two-hybrid screen using the C-terminal tail of p22phox as bait against a vascular smooth muscle cell cDNA library[lyle-2009-nox4-abstract]. This screen identified POLDIP2 as a novel p22phox binding partner. p22phox is an essential membrane-associated subunit of the NADPH oxidase (Nox) complex that is required for the stability and activity of several Nox isoforms including Nox1, Nox2, Nox3, and Nox4[lyle-2009-nox4-abstract].

Biochemical validation confirmed that POLDIP2 associates with p22phox, Nox1, and Nox4 and colocalizes with p22phox at sites of Nox4 localization including focal adhesions, stress fibers, and nuclear compartments[lyle-2009-nox4-abstract]. GST-pulldown assays demonstrated that radiolabeled POLDIP2 binds to GST-p22phox fusion proteins, and coimmunoprecipitation studies showed that endogenous POLDIP2 associates with p22phox in cells. The interaction of tagged POLDIP2 with Nox4 requires p22phox, as POLDIP2 coimmunoprecipitates with Nox4 in control cells but not in cells lacking p22phox[lyle-2009-nox4-abstract].

Functional Effects on Nox4 Activity

POLDIP2 substantially enhances Nox4 enzymatic activity. Overexpression of POLDIP2 increases Nox4-dependent reactive oxygen species production by approximately 3-fold[lyle-2009-nox4-abstract]. POLDIP2 positively regulates basal ROS production in vascular smooth muscle cells, with superoxide (O2-) increased by 86.3 +/- 15.6% and hydrogen peroxide (H2O2) increased by 40.7 +/- 4.5%[lyle-2009-nox4-abstract]. This effect is Nox4-dependent, as it is blocked when Nox4 is depleted by siRNA[lyle-2009-nox4-abstract]. Conversely, knockdown of POLDIP2 decreases both superoxide and hydrogen peroxide production[lyle-2009-nox4-abstract].

In vivo validation comes from studies of Poldip2 heterozygous mice (homozygous deletion being perinatally lethal). These animals show significantly decreased NADPH-dependent production of both O2- and H2O2 in the vasculature, confirming that POLDIP2 contributes to Nox4 activity in vivo[sutliff-2013-vascular-abstract]. The H2O2 produced through the POLDIP2-Nox4 pathway appears to serve important signaling functions, as supplementing cultured vascular smooth muscle cells from Poldip2+/- mice with H2O2 normalizes their extracellular matrix production[sutliff-2013-vascular-abstract].

Downstream Effects on Cell Signaling and Cytoskeleton

POLDIP2-Nox4-dependent ROS production has important downstream consequences for cell signaling and cytoskeletal organization. Overexpression of POLDIP2 activates Rho GTPase by approximately 180%, strengthens focal adhesions, and increases stress fiber formation[lyle-2009-nox4-abstract]. These phenotypic changes are blocked by dominant negative Rho, demonstrating that Rho activation lies downstream of POLDIP2-Nox4 signaling. Conversely, depletion of either POLDIP2 or Nox4 results in loss of focal adhesion and stress fiber structures, which can be rescued by expression of constitutively active Rho[lyle-2009-nox4-abstract].

More recent work has elucidated a specific mechanism by which the NOX4-POLDIP2 complex regulates cytoskeletal dynamics through direct oxidation of filamentous actin[cheng-2018-nox4-actin-abstract]. During integrin-mediated cell adhesion, F-actin undergoes oxidation through sulfenylation, with a peak occurring approximately 3 hours after cell attachment[cheng-2018-nox4-actin-abstract]. This oxidation is enhanced by POLDIP2 overexpression and inhibited by approximately 78-99% upon depletion of POLDIP2 or NOX4, or by scavenging H2O2 with catalase[cheng-2018-nox4-actin-abstract]. Silencing of POLDIP2 or NOX4 impairs the interaction between actin and vinculin, disturbing focal adhesion maturation and inhibiting cell migration[cheng-2018-nox4-actin-abstract]. Thus, integrin engagement activates the POLDIP2-Nox4 complex to oxidize actin, which modulates focal adhesion assembly.

Cell Migration Effects

Both overexpression and depletion of POLDIP2 block PDGF-induced vascular smooth muscle cell migration, indicating that optimal POLDIP2 levels are critical for normal cell motility[lyle-2009-nox4-abstract][hernandes-2017-review-fulltext]. Excessive POLDIP2 appears to prevent focal adhesion dissolution required for cell movement, while insufficient POLDIP2 prevents focal adhesion formation in the first place[hernandes-2017-review-fulltext]. This biphasic effect suggests that POLDIP2 may be a therapeutic target for vascular pathologies involving abnormal smooth muscle cell migration, such as restenosis and atherosclerosis[lyle-2009-nox4-abstract].

Differential Regulation of Nox Isoforms

Interestingly, POLDIP2's effects on different NADPH oxidase isoforms appear to be divergent. While POLDIP2 positively regulates Nox4 activity, studies on phagocyte NADPH oxidase 2 (Nox2) revealed an opposite effect[hernandes-2017-review-fulltext]. Using membranes from circulating resting neutrophils, ROS production by Nox2 was down-regulated approximately 2.5-fold by POLDIP2[hernandes-2017-review-fulltext]. This inhibitory effect on Nox2 appears to be mediated through interaction with p47phox rather than p22phox, representing a novel regulatory mechanism. These findings suggest that POLDIP2 could act as a tunable switch capable of differentially regulating NADPH oxidase isoforms, potentially orchestrating the level and type of ROS generated by different Nox enzymes in cells[hernandes-2017-review-fulltext].

Mitochondrial Functions

CLPXP Protease Adaptor

A major advance in understanding POLDIP2's mitochondrial functions came with the identification of POLDIP2/PDIP38 as the first mammalian adaptor protein for the mitochondrial AAA+ protease CLPXP[strack-2020-clpxp-abstract]. CLPXP is a conserved ATP-dependent protease consisting of CLPX, an AAA+ unfoldase that recognizes and unfolds target proteins, and CLPP, a serine protease that degrades the unfolded substrates[strack-2020-clpxp-abstract]. AAA+ proteases in bacteria use specialized cofactors called adaptor proteins to alter substrate recognition and specificity, but prior to the characterization of PDIP38, no such adaptor had been identified in mammalian mitochondria.

Human PDIP38 resides in the mitochondrial matrix where it colocalizes with CLPX[strack-2020-clpxp-abstract]. The N-terminal YccV-like domain of PDIP38 specifically interacts with CLPX through the adaptor docking loop within CLPX's N-terminal zinc binding domain[strack-2020-clpxp-abstract]. This interaction has multiple functional consequences: PDIP38 modulates the substrate specificity of CLPXP in vitro, and perhaps equally importantly, protects CLPX from degradation by the mitochondrial LON protease, thereby stabilizing cellular CLPX levels[strack-2020-clpxp-abstract].

Regulation of Lipoylation and Metabolic Adaptation

One of the most physiologically significant mitochondrial functions of POLDIP2 is its regulation of protein lipoylation and consequently of key TCA cycle enzymes[amanso-2018-lipoylation-abstract]. Lipoic acid is an essential cofactor for several mitochondrial enzyme complexes including pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (alphaKGDH), where it is covalently attached to lysine residues of the E2 subunits (DLAT and DLST, respectively).

POLDIP2 regulates lipoylation through a pathway involving CLPXP and the lipoic acid-activating enzyme ACSM1[amanso-2018-lipoylation-abstract]. When POLDIP2 levels are normal, it binds to CLPX and restrains CLPXP protease activity toward ACSM1. When POLDIP2 levels decrease, CLPXP becomes active and degrades ACSM1. Without ACSM1, lipoyl-AMP cannot be synthesized, preventing LIPT1 from transferring lipoyl groups to DLAT and DLST. The resulting decrease in PDH and alphaKGDH lipoylation inhibits these TCA cycle enzymes, suppressing mitochondrial respiration and reducing cellular alpha-ketoglutarate levels[amanso-2018-lipoylation-abstract].

Cells deficient in POLDIP2 show significantly reduced levels of lipoyl-DLAT and lipoyl-DLST, with corresponding decreases in PDH and alphaKGDH enzymatic activities[amanso-2018-lipoylation-abstract]. Importantly, forced expression of ACSM1 in POLDIP2-deficient cells rescues lipoylation levels, confirming that ACSM1 is the critical intermediate[amanso-2018-lipoylation-abstract].

This mechanism has important implications for cellular adaptation to hypoxia and cancer metabolism. POLDIP2 expression is down-regulated by hypoxia across multiple cell types, triggering the lipoylation deficit and subsequent inhibition of PDH and alphaKGDH[amanso-2018-lipoylation-abstract]. This metabolic rewiring contributes to HIF-1alpha stabilization through inhibition of alpha-ketoglutarate-dependent prolyl hydroxylases. Triple-negative breast cancer (TNBC) cells exhibit basal suppression of POLDIP2 and complete inhibition of DLAT/DLST lipoylation. Restoring POLDIP2 expression in TNBC cells increases mitochondrial respiration and reduces cancer cell growth rate[amanso-2018-lipoylation-abstract], suggesting a tumor suppressive role in some contexts.

Heme Biosynthesis Regulation

More recently, POLDIP2 has been identified as a heme-sensing adaptor that delivers aminolevulinic acid synthase (ALAS) for degradation by CLPXP[hernandes-2017-review-fulltext]. ALAS catalyzes the first and rate-limiting step of heme biosynthesis in mitochondria. By serving as an adaptor that responds to heme levels, POLDIP2 participates in feedback regulation of heme biosynthesis, linking POLDIP2 function to porphyria-related disorders caused by CLPX mutations[hernandes-2017-review-fulltext].

Vascular and Cardiovascular Phenotypes

Studies in Poldip2-deficient mice have revealed important roles for this protein in vascular structure and function. Because complete Poldip2 deletion is perinatally lethal (with only about 3% of expected homozygous knockout animals surviving to birth), most in vivo studies have utilized heterozygous animals with approximately 50% reduced protein levels[sutliff-2013-vascular-abstract][amanso-2014-knockout-abstract].

Poldip2 heterozygous mice show multiple vascular abnormalities[sutliff-2013-vascular-abstract]. Their aortas exhibit disordered and fragmented elastic lamellae when examined by transmission electron microscopy, along with excessive extracellular matrix deposition[sutliff-2013-vascular-abstract]. Vascular smooth muscle cells isolated from these animals secrete elevated levels of collagen I, an effect that can be normalized by supplementing culture medium with hydrogen peroxide[sutliff-2013-vascular-abstract]. This suggests that POLDIP2-Nox4-derived H2O2 normally suppresses excessive extracellular matrix production[sutliff-2013-vascular-abstract].

Functionally, aortas from Poldip2+/- mice show impaired contractile responses to both phenylephrine and potassium chloride stimulation, with maximal force reduced by approximately 48% and 44% respectively[sutliff-2013-vascular-abstract]. The combination of structural abnormalities (fragmented elastic lamellae, excess collagen) and decreased contractility results in increased arterial stiffness[sutliff-2013-vascular-abstract][hernandes-2017-review-fulltext]. Paradoxically, these structural changes may provide protection in certain disease contexts: Poldip2+/- mice demonstrate resistance to experimental aortic dilatation induced by calcium chloride treatment[sutliff-2013-vascular-abstract], and heterozygous animals show protection against injury-induced neointimal hyperplasia[hernandes-2017-review-fulltext].

POLDIP2 also promotes ischemia-induced collateral vessel formation, with heterozygous deletion impairing revascularization following femoral artery ligation[hernandes-2017-review-fulltext]. This suggests that appropriate POLDIP2 levels are required for adaptive angiogenesis.

Cell Cycle, Proliferation, and Mitotic Spindle Function

Poldip2 knockout mouse embryonic fibroblasts (MEFs) exhibit markedly reduced cellular growth rates[amanso-2014-knockout-abstract]. These cells show cell cycle arrest or delay in both G1 and G2/M phases, accompanied by decreased expression of cell cycle regulators cdk1 and Cyclin A2[amanso-2014-knockout-abstract][hernandes-2017-review-fulltext]. Additionally, Poldip2 knockout increases markers of autophagy in MEFs[amanso-2014-knockout-abstract], potentially as a compensatory response to metabolic dysfunction.

Beyond its roles during interphase, POLDIP2 also functions during mitosis. Studies using immunofluorescence microscopy demonstrated that PDIP38 localizes to the mitotic spindle throughout all stages of mitosis[klaile-2008-spindle-abstract]. Functional experiments using anti-PDIP38 antibody microinjection and siRNA silencing revealed that loss of PDIP38 function causes defects in spindle organization, aberrant chromosome segregation, and the formation of multinucleated cells[klaile-2008-spindle-abstract]. These findings indicate that PDIP38 plays distinct roles at different stages of the cell cycle: during S phase it facilitates DNA replication and damage tolerance, while during M phase it contributes to proper mitotic spindle organization and accurate chromosome segregation[klaile-2008-spindle-abstract].

The mechanisms underlying the proliferation defects observed in POLDIP2-deficient cells likely involve multiple functions: the DNA damage tolerance activities (required for efficient progression through S phase), the mitotic spindle organization function (required for accurate chromosome segregation), and the metabolic functions (required for mitochondrial ATP production). The observation that POLDIP2 depletion increases cell sensitivity to oxidative stress[maga-2013-pol-lambda-abstract] suggests that accumulation of unrepaired oxidative DNA damage may also contribute to the proliferation defect.

RNA Splicing and Alternative Splicing Regulation

An unexpected function for POLDIP2/PDIP38 emerged from studies examining its nuclear localization in response to DNA damage. While PDIP38 was expected to localize to UV-induced DNA repair foci given its established roles in translesion synthesis, researchers observed that in certain cell lines (HeLa and A549), UV irradiation instead triggers PDIP38 translocation to nuclear speckles where it colocalizes with the spliceosome marker SC35[wong-2013-splicing-abstract].

Nuclear speckles are subnuclear domains enriched in pre-mRNA splicing factors and serve as storage and assembly sites for the splicing machinery. The functional significance of PDIP38 localization to these structures was demonstrated by examining alternative splicing of MDM2, a key p53 regulator. UV treatment normally induces alternative splicing of MDM2, generating splice variants that affect p53 regulation and DNA damage responses. Cells expressing shRNA targeting PDIP38 showed greatly reduced UV-induced MDM2 alternative splicing, establishing that PDIP38 is required for this stress-induced splicing response[wong-2013-splicing-abstract]. Similar PDIP38 translocation and splicing effects occurred when cells were treated with the transcription inhibitors actinomycin D or alpha-amanitin, suggesting that PDIP38 responds broadly to transcriptional stress[wong-2013-splicing-abstract].

This splicing function appears to be cell-type specific: in MRC-5 fibroblasts, PDIP38 localizes to UV repair foci consistent with its translesion synthesis role, while in HeLa and A549 cells it preferentially translocates to spliceosomes[wong-2013-splicing-abstract]. This context-dependent behavior exemplifies the moonlighting nature of POLDIP2 and raises questions about how cells regulate the partitioning of this protein among its various functional compartments.

Neurological Functions and Disease Associations

POLDIP2 has been implicated in several neurological contexts, though some findings remain controversial. Studies in neuronal cell lines demonstrated that POLDIP2 expression is increased in response to multiple stress signals including amyloid-beta (Abeta), TNF-alpha, and hydrogen peroxide[kim-2015-tau-abstract]. Importantly, POLDIP2 was identified through cDNA library screening as a factor that promotes Tau aggregation. Ectopic expression of POLDIP2 enhanced Tau aggregate formation without affecting Tau phosphorylation, while POLDIP2 knockdown alleviated ROS-induced Tau aggregation[kim-2015-tau-abstract]. Mechanistically, POLDIP2 overexpression impaired both autophagy and proteasome activities, with these effects mapping to the DUF525 domain[kim-2015-tau-abstract].

In vivo validation came from Drosophila models of tauopathy. Knockdown of the Drosophila POLDIP2 homolog (CG12162) attenuated the rough eye phenotype induced by human Tau overexpression and extended the lifespan of flies expressing disease-associated Tau(R406W)[kim-2015-tau-abstract]. These findings suggest that POLDIP2 inhibition might be neuroprotective in tauopathies.

However, some reports have suggested opposite effects. siRNA against Poldip2 was reported to alleviate H2O2-induced Tau aggregation in SH-SY5Y human neuroblastoma cells[hernandes-2017-review-fulltext], consistent with a pro-aggregation role. Conversely, other in vitro studies found that purified PolDIP2 actually inhibits Tau oligomer and fibril formation in biochemical assays[hernandes-2017-review-fulltext]. These apparently contradictory findings may reflect different experimental systems (cellular versus cell-free), the complex relationship between POLDIP2's effects on protein quality control pathways versus direct protein-protein interactions, or context-dependent functions.

In cerebrovascular disease, Poldip2 heterozygous mice exhibited significantly decreased Evans blue dye extravasation following cerebral ischemia, indicating reduced blood-brain barrier permeability and improved survival[hernandes-2017-review-fulltext]. This protective effect in heterozygotes likely relates to the reduced Nox4-dependent ROS production, suggesting that POLDIP2 inhibition might be beneficial in ischemic stroke through reduction of oxidative stress at the blood-brain barrier.

Open Questions

Despite significant progress in understanding POLDIP2 biology, several important questions remain unresolved.

First, the relative importance of POLDIP2's diverse functions in different physiological and pathological contexts is unclear. The protein has documented roles in at least three major cellular compartments (nucleus, mitochondria, cytoplasm/focal adhesions), and the phenotypes of Poldip2-deficient cells and organisms likely reflect the combined loss of multiple functions. Tissue-specific and inducible knockout models, along with structure-function studies using domain-specific mutations, will be needed to dissect the individual contributions.

Second, the functional relationship between the 42 kDa and 37 kDa forms of POLDIP2 remains undefined. Whether these forms have distinct interaction partners and functions, and how the balance between them is regulated, are important open questions[hernandes-2017-review-fulltext]. The observation that the N-terminal region required for PrimPol interaction overlaps with the mitochondrial targeting sequence suggests that the nuclear and mitochondrial forms may have non-overlapping functions[guilliam-2016-primpol-abstract].

Third, how POLDIP2 localization is regulated in response to cellular conditions (proliferation state, oxidative stress, DNA damage) requires further investigation. The finding that POLDIP2 contains a potential redox-sensing cysteine residue within an internal channel[kulik-2021-structure-abstract] raises the possibility of direct redox regulation, but this remains to be demonstrated functionally.

Fourth, the relationship between POLDIP2's role in DNA damage tolerance and cancer remains complex. On one hand, POLDIP2 promotes error-prone translesion synthesis which could contribute to mutagenesis; on the other hand, low POLDIP2 in triple-negative breast cancer cells contributes to metabolic dysfunction that may promote tumor growth[amanso-2018-lipoylation-abstract]. Expression correlation studies have yielded mixed results, with some reports showing correlation with breast cancer tumors and others showing inverse correlation with lung cancer risk[hernandes-2017-review-fulltext].

Fifth, the transcriptional regulation of POLDIP2 and the mechanisms controlling its expression in response to hypoxia and other stresses are poorly characterized. Understanding these regulatory pathways will be important for evaluating POLDIP2 as a potential therapeutic target.

Finally, POLDIP2 interacts with over 40 documented protein partners[hernandes-2017-review-fulltext], and this interaction network is likely incomplete. How these numerous interactions are coordinated spatially and temporally, and whether POLDIP2 functions as a signaling hub that integrates information from multiple pathways, represents an exciting area for future investigation.

References

1. liu-2003-pdip38-discovery-abstract: Liu L, Rodriguez-Belmonte EM, Mazloum N, Xie B, Lee MY. (2003) Identification of a novel protein, PDIP38, that interacts with the p50 subunit of DNA polymerase delta and proliferating cell nuclear antigen. J Biol Chem 278(12):10041-10047. PMID: 12522211. DOI: 10.1074/jbc.M208694200

2. hernandes-2017-review-fulltext: Hernandes MS, Lassegue B, Griendling KK. (2017) Polymerase delta-interacting protein 2: a multifunctional protein. J Cardiovasc Pharmacol 69(6):335-342. PMID: 28574953. PMCID: PMC5556945. DOI: 10.1097/FJC.0000000000000465

3. lyle-2009-nox4-abstract: Lyle AN, Deshpande NN, Taniyama Y, Seidel-Rogol B, Pounkova L, Du P, Papaharalambus C, Lassegue B, Griendling KK. (2009) Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circ Res 105(3):249-259. PMID: 19574552. PMCID: PMC2744198. DOI: 10.1161/CIRCRESAHA.109.193722

4. guilliam-2016-primpol-abstract: Guilliam TA, Bailey LJ, Brissett NC, Doherty AJ. (2016) PolDIP2 interacts with human PrimPol and enhances its DNA polymerase activities. Nucleic Acids Res 44(7):3317-3329. PMID: 26984527. PMCID: PMC4838387. DOI: 10.1093/nar/gkw175

5. maga-2013-pol-lambda-abstract: Maga G, Villani E, Locatelli GA, Crespan E, Shevelev I, Jiricny J, Hubscher U. (2013) DNA polymerase delta-interacting protein 2 is a processivity factor for DNA polymerase lambda during 8-oxo-7,8-dihydroguanine bypass. Proc Natl Acad Sci USA 110(47):18850-18855. PMID: 24191025. PMCID: PMC3839753. DOI: 10.1073/pnas.1308760110

6. sutliff-2013-vascular-abstract: Sutliff RL, Hilenski J, Amanso DB, et al. (2013) Polymerase delta interacting protein 2 sustains vascular structure and function. Arterioscler Thromb Vasc Biol 33(9):2154-2161. PMID: 23825363. PMCID: PMC3837414. DOI: 10.1161/ATVBAHA.113.301913

7. kulik-2021-structure-abstract: Kulik AA, Maruszczak KK, Thomas DC, Nabi-Aldridge NLA, Carr M, Bingham RJ, Cooper CDO. (2021) Crystal structure and molecular dynamics of human POLDIP2, a multifaceted adaptor protein in metabolism and genome stability. Protein Sci 30(6):1196-1209. PMID: 33884680. PMCID: PMC8138528. DOI: 10.1002/pro.4085. PDB: 6Z9C

8. strack-2020-clpxp-abstract: Strack PR, Brodie EJ, Zhan H, et al. (2020) Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP. Commun Biol 3(1):666. PMID: 33184454. PMCID: PMC7665182. DOI: 10.1038/s42003-020-01358-6

9. amanso-2014-knockout-abstract: Amanso DB, Seidel-Rogol SS, Griendling KK. (2014) Poldip2 knockout results in perinatal lethality, reduced cellular growth and increased autophagy of mouse embryonic fibroblasts. PLOS ONE 9(5):e96657. PMID: 24797518. PMCID: PMC4010529. DOI: 10.1371/journal.pone.0096657

10. amanso-2018-lipoylation-abstract: Amanso DB, Seidel-Rogol SS, Shao Y, Bhayani I, San Martin A, Griendling KK. (2018) Poldip2 is an oxygen-sensitive protein that controls PDH and alphaKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer. Proc Natl Acad Sci USA 115(8):1789-1794. PMID: 29437960. PMCID: PMC5828627. DOI: 10.1073/pnas.1720693115

11. tissier-2019-tls-vs-ts-abstract: Tissier A, Lemoine R, Yamada K, et al. (2019) PDIP38/PolDIP2 controls the DNA damage tolerance pathways by increasing the relative usage of translesion DNA synthesis over template switching. PLOS ONE 14(3):e0213383. PMID: 30817784. PMCID: PMC6402704. DOI: 10.1371/journal.pone.0213383

12. cheng-2018-nox4-actin-abstract: Cheng G, Amanso DB, et al. (2018) NOX4 (NADPH Oxidase 4) and Poldip2 (Polymerase delta-Interacting Protein 2) Induce Filamentous Actin Oxidation and Promote Its Interaction With Vinculin During Integrin-Mediated Cell Adhesion. Arterioscler Thromb Vasc Biol 38(11):2651-2666. PMID: 30354218. DOI: 10.1161/ATVBAHA.118.311668

13. klaile-2008-spindle-abstract: Klaile E, Kukalev A, Obrink B, Muller MM. (2008) PDIP38 is a novel mitotic spindle-associated protein that affects spindle organization and chromosome segregation. Cell Cycle 7(20):3180-3186. PMID: 18843206. DOI: 10.4161/cc.7.20.6813

14. wong-2013-splicing-abstract: Wong A, Zhang S, Mordue D, Wu JM, Zhang Z, Darzynkiewicz Z, Lee EYC, Lee MYWT. (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 12(19):3184-3193. PMID: 23989611. PMCID: PMC3865014. DOI: 10.4161/cc.26221

15. kim-2015-tau-abstract: Kim N, et al. (2015) Essential role of POLDIP2 in Tau aggregation and neurotoxicity via autophagy/proteasome inhibition. Biochem Biophys Res Commun PMID: 25930997

Citations

1. amanso-2014-knockout-abstract.md
2. amanso-2018-lipoylation-abstract.md
3. cheng-2018-nox4-actin-abstract.md
4. guilliam-2016-primpol-abstract.md
5. hernandes-2017-review-fulltext.md
6. kim-2015-tau-abstract.md
7. klaile-2008-spindle-abstract.md
8. kulik-2021-structure-abstract.md
9. liu-2003-pdip38-discovery-abstract.md
10. lyle-2009-nox4-abstract.md
11. maga-2013-pol-lambda-abstract.md
12. strack-2020-clpxp-abstract.md
13. sutliff-2013-vascular-abstract.md
14. tissier-2019-tls-vs-ts-abstract.md
15. wong-2013-splicing-abstract.md

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Human POLDIP2 (Q9Y2S7)

Identity verification and nomenclature
- Target confirmed as human polymerase delta–interacting protein 2 (POLDIP2; also historically PDIP38/PolDIP2), originally identified as a binding partner of the p50 subunit of DNA polymerase δ and associated with PCNA in the nucleus (supporting the polymerase delta–interacting identity) (wuttinontananchai2025genomewidecrisprscreen pages 13-14, wuttinontananchai2025genomewidecrisprscreen pages 11-12). The requested organism context (Homo sapiens) and gene symbol match the literature cited below. Domain-level details such as ApaG/DUF525 and hemimethylated-DNA-binding–like folds are consistent with the UniProt record provided by the requester, but recent sources in the gathered evidence do not further elaborate these domains; thus, domain inferences here remain based on UniProt and are noted as such.

Key concepts and definitions (current understanding)
- Multifunctional scaffold at the interface of DNA replication/repair, replication stress tolerance, RNA processing, and redox signaling: In the nucleus, POLDIP2 binds Pol δ (p50) and associates with PCNA, linking it to coordination of DNA replication/repair and translesion synthesis via reported interaction with Pol η. It also functionally connects to repriming through PrimPol, though recruitment to UV damage sites can be context-dependent. Beyond DNA metabolism, it can translocate to spliceosomes and regulate UV-induced alternative splicing (e.g., MDM2). In mitochondria and cytoplasm, POLDIP2 interacts with p22phox to enhance NOX4 activity and ROS production, integrating replication stress biology with cellular redox signaling (wuttinontananchai2025genomewidecrisprscreen pages 11-12, wuttinontananchai2025genomewidecrisprscreen pages 13-14).

Recent developments and latest research (2023–2025)
- Post-transcriptional regulation via alternative polyadenylation (APA): A 2025 genome-wide CRISPR screen identified POLDIP2 as a novel APA regulator that globally affects 3′ UTR selection. Knockdown increased CD47 protein and favored the short 3′ UTR isoform, with transcriptome-wide bidirectional APA changes, suggesting a scaffolding role in PAS selection despite lacking a canonical RNA-binding domain (Scientific Reports; Aug 2025; https://doi.org/10.1038/s41598-025-14782-7) (wuttinontananchai2025genomewidecrisprscreen pages 11-12).
- Endothelial inflammation and COVID-19 pathobiology: A 2025 preprint reports that Poldip2 haploinsufficiency in hACE2 mice attenuates SARS‑CoV‑2–induced disease severity without altering viral load, reducing neutrophil infiltration and inflammatory cytokines. The study frames POLDIP2 as a modulator of vascular inflammation, consistent with prior BBB/vascular permeability literature referenced therein (bioRxiv; Jun 2025; https://doi.org/10.1101/2025.06.17.657579) (hu2025poldip2deficiencyattenuates pages 16-19).
- AMD-related oxidative stress in human RPE: CRISPR/Cas9 POLDIP2 knockout in ARPE‑19 cells reduced mitochondrial superoxide (MitoSOX) and was associated with SOD2 upregulation and immune/complement transcriptional changes, supporting a role for POLDIP2 in retinal oxidative stress pathways relevant to AMD (Aging; Feb 2023; https://doi.org/10.18632/aging.204522) (nguyen2023knockoutofamdassociated pages 8-10, nguyen2023knockoutofamdassociated pages 13-14).

Biochemical functions and interactions
- Replication/repair machinery: POLDIP2 binds the p50 subunit of Pol δ and associates with PCNA, situating it within replisome-associated processes, including DNA damage tolerance/TLS via Pol η and coordination with repriming polymerase PrimPol. Reports differ on UV-damage recruitment, indicating regulation may be context- or stimulus-specific (wuttinontananchai2025genomewidecrisprscreen pages 11-12, wuttinontananchai2025genomewidecrisprscreen pages 13-14).
- Redox signaling: POLDIP2 binds the C-terminal tail of p22phox to enhance NOX4 enzymatic activity, increasing ROS output. This biochemical interaction provides a molecular pathway linking POLDIP2 to vascular cell signaling, barrier function, and inflammatory responses (wuttinontananchai2025genomewidecrisprscreen pages 11-12).
- RNA processing: POLDIP2 can relocalize to spliceosomes and regulate alternative splicing (e.g., MDM2) under UV; more recently, it acts as a global APA regulator that alters 3′ UTR landscapes, influencing protein output (wuttinontananchai2025genomewidecrisprscreen pages 11-12).

Roles in DNA replication/repair and replication stress tolerance
- By interacting with PCNA and TLS polymerases, and by modulating PrimPol-dependent repriming, POLDIP2 is positioned to facilitate replication across DNA lesions and to integrate replication stress responses. The functional footprint includes coordination of DNA replication and repair and broader replication stress/DNA damage response programs (wuttinontananchai2025genomewidecrisprscreen pages 11-12, wuttinontananchai2025genomewidecrisprscreen pages 13-14).

Mitochondrial functions and ROS regulation
- POLDIP2 promotes NOX4-dependent ROS generation via p22phox binding; in human retinal pigment epithelium, POLDIP2 knockout reduces mitochondrial superoxide and upregulates SOD2, indicating POLDIP2 as a positive regulator of oxidative tone and linking it to retinal disease biology (wuttinontananchai2025genomewidecrisprscreen pages 11-12, nguyen2023knockoutofamdassociated pages 8-10).

Subcellular localization
- Nuclear and mitochondrial/cytoplasmic pools: POLDIP2 displays subcellular dynamics, with nuclear localization for DNA replication/repair and RNA processing roles, and mitochondrial/cytosolic activities for ROS regulation via NOX4–p22phox (wuttinontananchai2025genomewidecrisprscreen pages 11-12).

Pathway integration
- DNA replication and damage tolerance: Integration with Pol δ, PCNA, TLS (Pol η), and PrimPol positions POLDIP2 within replication fork progression, repriming, and lesion bypass mechanisms (wuttinontananchai2025genomewidecrisprscreen pages 11-12, wuttinontananchai2025genomewidecrisprscreen pages 13-14).
- Redox/vascular signaling: Through NOX4 activation, POLDIP2 contributes to ROS-dependent signaling cascades that affect endothelial/vascular function and inflammation (wuttinontananchai2025genomewidecrisprscreen pages 11-12, hu2025poldip2deficiencyattenuates pages 16-19).
- Post-transcriptional gene regulation: POLDIP2’s roles in splicing and APA broaden its regulatory scope to transcript fate and protein expression profiles during stress responses (wuttinontananchai2025genomewidecrisprscreen pages 11-12).

Current applications and real-world implementations
- Disease modeling/therapeutic exploration:
- AMD: Human RPE POLDIP2 knockout models demonstrate reduced mitochondrial superoxide and altered inflammatory/complement gene expression, motivating POLDIP2 as a potential modulator of retinal oxidative stress and a candidate for mechanistic/therapeutic studies (Aging; 2023; https://doi.org/10.18632/aging.204522) (nguyen2023knockoutofamdassociated pages 8-10, nguyen2023knockoutofamdassociated pages 13-14).
- COVID-19 inflammation: Genetic reduction of Poldip2 mitigated disease severity in a mouse SARS‑CoV‑2 model, suggesting that POLDIP2-dependent vascular inflammation could be a target; this remains preclinical (bioRxiv; 2025; https://doi.org/10.1101/2025.06.17.657579) (hu2025poldip2deficiencyattenuates pages 16-19).
- APA biomarkers/regulators: The 2025 CRISPR screen positions POLDIP2 as a regulator of APA with measurable effects on CD47 surface expression, indicating utility in functional genomics screens of post-transcriptional regulation and potentially in immunobiology contexts where CD47 is relevant (Sci Rep; 2025; https://doi.org/10.1038/s41598-025-14782-7) (wuttinontananchai2025genomewidecrisprscreen pages 11-12).

Expert opinions and analysis from authoritative sources
- A 2025 peer-reviewed study frames POLDIP2 as a multifunctional, subcellularly dynamic scaffold that coordinates DNA replication/repair, RNA processing (splicing/APA), and mitochondrial ROS production via NOX4. The same study synthesizes earlier biochemical work and presents new APA data, emphasizing scaffolding as a unifying principle (Sci Rep; 2025; https://doi.org/10.1038/s41598-025-14782-7) (wuttinontananchai2025genomewidecrisprscreen pages 11-12).
- Preclinical vascular studies suggest that POLDIP2’s redox functions underlie endothelial barrier regulation and inflammation relevant to infectious and ischemic insults, aligning with prior endothelial/BBB permeability literature referenced in 2025 work (bioRxiv; 2025; https://doi.org/10.1101/2025.06.17.657579) (hu2025poldip2deficiencyattenuates pages 16-19).

Relevant statistics and data from recent studies
- AMD/RPE model: POLDIP2 knockout ARPE‑19 cells showed a reduction in mitochondrial superoxide measured by MitoSOX (2 biological experiments, each with 3 technical replicates) and increased SOD2 expression; transcriptomics revealed immune/complement pathway changes (Aging; 2023; https://doi.org/10.18632/aging.204522) (nguyen2023knockoutofamdassociated pages 8-10).
- APA regulation: POLDIP2 knockdown increased CD47 protein abundance and shifted isoform usage toward the short 3′ UTR; transcriptome-wide effects included both 3′ UTR shortening and lengthening, highlighting a global role in APA (Sci Rep; 2025; https://doi.org/10.1038/s41598-025-14782-7) (wuttinontananchai2025genomewidecrisprscreen pages 11-12).
- COVID-19 model: Poldip2+/− hACE2 mice exhibited attenuated disease severity metrics (reduced neutrophil infiltration/chemokines) with unchanged viral load; quantitative details are in the preprint’s figures and supplements (bioRxiv; 2025; https://doi.org/10.1101/2025.06.17.657579) (hu2025poldip2deficiencyattenuates pages 16-19).

Disease relevance
- Vascular permeability and inflammation: Genetic reduction of Poldip2 ameliorates inflammatory injury in SARS‑CoV‑2 infection models and aligns with prior observations that POLDIP2 regulates endothelial/BBB permeability through ROS-linked effects (hu2025poldip2deficiencyattenuates pages 16-19).
- Age-related macular degeneration (AMD): POLDIP2 KO decreases mitochondrial superoxide and reshapes immune/complement transcriptional programs in human RPE, supporting a contributory role to AMD pathogenesis via oxidative signaling (nguyen2023knockoutofamdassociated pages 8-10, nguyen2023knockoutofamdassociated pages 13-14).
- Cancer and replication stress: Through interactions with PCNA/TLS polymerases and regulation of PrimPol-mediated repriming, POLDIP2 interfaces with replication stress tolerance mechanisms relevant to tumor biology; recent APA findings further implicate it in post-transcriptional regulation impacting oncogenic pathways (wuttinontananchai2025genomewidecrisprscreen pages 11-12, wuttinontananchai2025genomewidecrisprscreen pages 13-14).

Limitations and open questions
- Structural domain details (e.g., ApaG/DUF525; hemimethylated DNA-binding–like folds) and high-resolution structures were not detailed in the recent sources captured here; interpretations relying on domain architecture are therefore limited to UniProt annotations provided by the requester and should be updated as structural studies emerge (wuttinontananchai2025genomewidecrisprscreen pages 11-12, wuttinontananchai2025genomewidecrisprscreen pages 13-14).
- Some vascular/BBB claims are based on a 2025 preprint that references earlier peer‑reviewed studies; while consistent with prior literature, the specific new results await peer review (hu2025poldip2deficiencyattenuates pages 16-19).

References (with URLs and publication dates)
- Wuttinontananchai C, Yamamoto J, Sakamoto S, Yamaguchi Y. Genome-wide CRISPR screen for human factors involved in alternative polyadenylation based on differential localization of CD47. Scientific Reports. Aug 2025. https://doi.org/10.1038/s41598-025-14782-7 (wuttinontananchai2025genomewidecrisprscreen pages 11-12)
- Hu R, Valdivia A, White T, et al. Poldip2 deficiency attenuates disease severity in a mouse model of COVID-19. bioRxiv. Jun 2025. https://doi.org/10.1101/2025.06.17.657579 (hu2025poldip2deficiencyattenuates pages 16-19)
- Nguyen T, Urrutia-Cabrera D, Wang L, et al. Knockout of AMD-associated gene POLDIP2 reduces mitochondrial superoxide in human retinal pigment epithelial cells. Aging. Feb 2023;15:1713–1733. https://doi.org/10.18632/aging.204522 (nguyen2023knockoutofamdassociated pages 8-10, nguyen2023knockoutofamdassociated pages 13-14)
- Additional background on Pol δ/PCNA/TLS/PrimPol and historical PDIP38 nomenclature summarized in the Scientific Reports 2025 article’s literature context (wuttinontananchai2025genomewidecrisprscreen pages 13-14).

References

1. (wuttinontananchai2025genomewidecrisprscreen pages 13-14): Chayanin Wuttinontananchai, Junichi Yamamoto, Satoshi Sakamoto, and Yuki Yamaguchi. Genome-wide crispr screen for human factors involved in alternative polyadenylation based on differential localization of cd47. Scientific Reports, Aug 2025. URL: https://doi.org/10.1038/s41598-025-14782-7, doi:10.1038/s41598-025-14782-7. This article has 1 citations and is from a peer-reviewed journal.

2. (wuttinontananchai2025genomewidecrisprscreen pages 11-12): Chayanin Wuttinontananchai, Junichi Yamamoto, Satoshi Sakamoto, and Yuki Yamaguchi. Genome-wide crispr screen for human factors involved in alternative polyadenylation based on differential localization of cd47. Scientific Reports, Aug 2025. URL: https://doi.org/10.1038/s41598-025-14782-7, doi:10.1038/s41598-025-14782-7. This article has 1 citations and is from a peer-reviewed journal.

3. (hu2025poldip2deficiencyattenuates pages 16-19): Ruinan Hu, Alejandra Valdivia, Taylor White, Willy Ju, Maegan L. Brockman, Zhan Zhang, Hongyan Qu, Georgette Gafford, Giji Joseph, Samantha Burton, Leda Bassit, Tysheena P. Charles, Rebecca D. Levit, Cynthia A. Derdeyn, Kathy K. Griendling, Bernard Lassègue, and Marina S. Hernandes. Poldip2 deficiency attenuates disease severity in a mouse model of covid-19. bioRxiv, Jun 2025. URL: https://doi.org/10.1101/2025.06.17.657579, doi:10.1101/2025.06.17.657579. This article has 0 citations and is from a poor quality or predatory journal.

4. (nguyen2023knockoutofamdassociated pages 8-10): Tu Nguyen, Daniel Urrutia-Cabrera, Luozixian Wang, Jarmon G. Lees, Jiang-Hui Wang, Sandy S.C. Hung, Alex W. Hewitt, Thomas L. Edwards, Sam McLenachan, Fred K. Chen, Shiang Y. Lim, Chi D. Luu, Robyn Guymer, and Raymond C.B. Wong. Knockout of amd-associated gene poldip2 reduces mitochondrial superoxide in human retinal pigment epithelial cells. Aging, 15:1713-1733, Feb 2023. URL: https://doi.org/10.18632/aging.204522, doi:10.18632/aging.204522. This article has 2 citations and is from a peer-reviewed journal.

5. (nguyen2023knockoutofamdassociated pages 13-14): Tu Nguyen, Daniel Urrutia-Cabrera, Luozixian Wang, Jarmon G. Lees, Jiang-Hui Wang, Sandy S.C. Hung, Alex W. Hewitt, Thomas L. Edwards, Sam McLenachan, Fred K. Chen, Shiang Y. Lim, Chi D. Luu, Robyn Guymer, and Raymond C.B. Wong. Knockout of amd-associated gene poldip2 reduces mitochondrial superoxide in human retinal pigment epithelial cells. Aging, 15:1713-1733, Feb 2023. URL: https://doi.org/10.18632/aging.204522, doi:10.18632/aging.204522. This article has 2 citations and is from a peer-reviewed journal.

Citations

1. wuttinontananchai2025genomewidecrisprscreen pages 11-12
2. nguyen2023knockoutofamdassociated pages 8-10
3. wuttinontananchai2025genomewidecrisprscreen pages 13-14
4. nguyen2023knockoutofamdassociated pages 13-14
5. https://doi.org/10.1038/s41598-025-14782-7
6. https://doi.org/10.1101/2025.06.17.657579
7. https://doi.org/10.18632/aging.204522
8. https://doi.org/10.1038/s41598-025-14782-7,
9. https://doi.org/10.1101/2025.06.17.657579,
10. https://doi.org/10.18632/aging.204522,

Polymerase δ-Interacting Protein 2 (POLDIP2) – Function, Localization, and Biological Roles

Gene and Protein Overview

POLDIP2 (Polymerase delta-interacting protein 2) is a human gene on chromosome 17q11.2 encoding a multifunctional protein of 368 amino acids (pmc.ncbi.nlm.nih.gov) (www.frontiersin.org). It was originally identified in 2003 as a 38 kDa protein (“PDIP38”) that binds the p50 subunit of DNA polymerase δ and the sliding clamp PCNA (pmc.ncbi.nlm.nih.gov). POLDIP2 is also known by synonyms PDIP38, p38, and Mitogenin-1 (pmc.ncbi.nlm.nih.gov). The protein is synthesized as a precursor with an N-terminal mitochondrial targeting sequence (MTS) and is processed to a mature ~37 kDa form upon import into mitochondria (pmc.ncbi.nlm.nih.gov). Structurally, POLDIP2 contains two conserved domains: an N-terminal YccV-like domain (also called a hemimethylated DNA-binding domain) and a C-terminal DUF525 domain (pmc.ncbi.nlm.nih.gov) (www.nature.com). The DUF525 region is shared with certain F-box proteins and bacterial ApaG proteins and is thought to mediate protein–protein interactions (pmc.ncbi.nlm.nih.gov). The YccV-like domain adopts an SH3-like β-barrel fold and may confer DNA-binding capacity (pmc.ncbi.nlm.nih.gov) (www.nature.com), though POLDIP2’s direct DNA-binding in human cells remains to be demonstrated. Notably, bioinformatic analysis has identified three putative PCNA-interacting motifs in POLDIP2’s sequence (www.frontiersin.org), consistent with its ability to bind PCNA. POLDIP2 is highly conserved across metazoans but is absent in bacteria, fungi, and plants (pmc.ncbi.nlm.nih.gov), highlighting its specialized role in multicellular eukaryotes.

Subcellular Localization and Dynamics

POLDIP2 has a dynamic subcellular localization, residing in multiple cellular compartments depending on cell type and conditions. Mitochondria are a principal site: the protein contains an N-terminal presequence that directs its import into the mitochondrial matrix (www.nature.com) (www.nature.com). In fact, experiments show that endogenous POLDIP2 localizes almost exclusively to mitochondria in many cells (e.g. smooth muscle, epithelial, fibroblast cells) when properly targeted (pmc.ncbi.nlm.nih.gov). Consistently, in vitro import assays confirm POLDIP2 is imported into isolated mitochondria in a membrane potential–dependent manner and processed to a mature intramitochondrial form (www.nature.com) (www.nature.com). However, a smaller fraction of POLDIP2 can also be found in the nucleus and cytoplasm under certain conditions (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Early studies using tagged POLDIP2 (which may inadvertently prevent mitochondrial import) observed the protein in the nucleus, cytosol, and even at the plasma membrane (www.nature.com). In proliferating cells, POLDIP2’s distribution appears cell-cycle regulated: it accumulates in the nucleus during G₂/M through G₁, suggesting a role in cell division (pmc.ncbi.nlm.nih.gov). In vascular smooth muscle cells and some epithelial cells, POLDIP2 also localizes to focal adhesions and along actin stress fibers in the cytoskeleton (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Intriguingly, a cell adhesion receptor, CEACAM1 (CD66a), directly interacts with POLDIP2 and can modulate its trafficking between the cell surface and nucleus (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In quiescent cells, engagement of CEACAM1 sequesters POLDIP2 outside the nucleus, whereas during proliferation POLDIP2 shifts to nuclear sites (pmc.ncbi.nlm.nih.gov). These findings indicate that POLDIP2’s localization is dynamic and context-dependent, enabling it to participate in different cellular processes in different compartments (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). (Notably, the major pool of endogenous POLDIP2 is often mitochondrial, with one study estimating ~68% cytosolic, 20% nuclear, and ~11% mitochondrial distribution in certain cell lines (pmc.ncbi.nlm.nih.gov), while other reports find it predominantly mitochondrial (pmc.ncbi.nlm.nih.gov). Differences may arise from cell type or detection methods.) The ability of POLDIP2 to shuttle between mitochondria, nucleus, and other locales underlies its multi-functional role in the cell.

Role in DNA Replication and Repair

POLDIP2 was first characterized through its connection to DNA polymerase δ, implying a role in DNA replication or repair. Polymerase δ (Polδ) is a major replicative DNA polymerase, and POLDIP2 binds to its p50 subunit (also called Polδ subunit 2) both in vitro and in vivo (pmc.ncbi.nlm.nih.gov). POLDIP2 also binds PCNA (the processivity factor for Polδ) via conserved PCNA-binding motifs (pmc.ncbi.nlm.nih.gov) (www.frontiersin.org). Although POLDIP2 is not an essential subunit of the replication machinery, it appears to act as an auxiliary factor that can influence replication under stress conditions. For example, translesion DNA synthesis (TLS) – a pathway that allows specialized DNA polymerases to bypass lesions – is facilitated by POLDIP2. POLDIP2 interacts with multiple TLS polymerases including Polη, Polζ, Rev1, and Polλ (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). It binds the ubiquitin-binding domain of Polη that normally helps Polη dock at ubiquitinated PCNA, suggesting POLDIP2 may aid the polymerase switch during damage bypass (pmc.ncbi.nlm.nih.gov). Indeed, silencing POLDIP2 causes an accumulation of Polη foci in nuclei (even without DNA damage) and makes cells more sensitive to UV-induced damage (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This supports the idea that POLDIP2 helps regulate the hand-off between Polδ and TLS polymerases at stalled forks (pmc.ncbi.nlm.nih.gov).

Experimental studies in 2013 demonstrated that POLDIP2 enhances the DNA synthesis activity of Polλ and Polη specifically during lesion bypass. Maga et al. (2013) showed POLDIP2 physically associates with Polλ and increases the processivity and efficiency of Polλ and Polη when copying over oxidative DNA lesions like 8-oxo-guanine (pmc.ncbi.nlm.nih.gov). In biochemical assays, adding POLDIP2 stimulated the ability of Polη and Polλ to synthesize DNA across 8-oxo-G, abasic sites, and thymine dimers, whereas other DNA polymerases (Polβ, Polι) were not stimulated (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). POLDIP2 also modestly stimulates Polδ’s activity without reducing fidelity, suggesting it might help Polδ itself or facilitate switching to Polλ at an oxidized base (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Cells lacking POLDIP2 showed increased sensitivity to oxidative DNA damage, a phenotype exacerbated if Polλ was also absent, indicating POLDIP2 and Polλ function in the same error-free repair pathway (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Separately, POLDIP2 has been shown to interact with the primase-polymerase PrimPol, an enzyme that reprimes stalled forks. In vitro, POLDIP2 binding enhances PrimPol’s DNA polymerase activity and DNA-binding ability (www.frontiersin.org) (www.frontiersin.org). Consistent with this, loss of POLDIP2 slows replication fork progression after UV damage, linking POLDIP2 to replication stress tolerance via PrimPol and TLS polymerases (academic.oup.com) (academic.oup.com).

Overall, POLDIP2 is emerging as a regulator of DNA replication and repair, particularly under conditions of DNA damage. By binding Polδ and PCNA, it may stabilize or organize the replication fork, and by interacting with TLS polymerases and PrimPol, it promotes efficient bypass of lesions and fork restart (www.frontiersin.org) (www.frontiersin.org). One study even found POLDIP2 interacts with the E7 oncoprotein of HPV16 and can modulate Polδ activity during viral DNA replication (www.frontiersin.org) (www.frontiersin.org), suggesting a role in host–virus replication dynamics. Taken together, while POLDIP2 is not an enzyme, it serves as an adapter or “switch” factor in the nucleus – coordinating polymerase exchange and maintaining genome stability during replication and repair.

Role in Mitochondrial Function and Metabolism

Beyond the nucleus, a critical function of POLDIP2 occurs in mitochondria. POLDIP2 is a nuclear-encoded mitochondrial protein that localizes to the matrix and partners with the mitochondrial AAA⁺ protease CLPXP (Caseinolytic protease P). Recent research has illuminated POLDIP2’s role as a proteostasis adaptor within mitochondria. In 2020, Deepa et al. solved POLDIP2’s domain structure and showed the N-terminal YccV-like domain specifically binds to the N-terminal docking region of the CLPX subunit (www.nature.com) (www.nature.com). The C-terminal DUF525 domain forms an immunoglobulin-like fold but its binding targets are not fully defined (www.nature.com). POLDIP2 itself is stably imported into the matrix and is neither degraded by CLP protease nor does it disrupt the CLPXP complex (www.nature.com) (www.nature.com). Instead, POLDIP2 modulates CLPXP’s activity and substrate specificity. It was found to protect CLPX from degradation by the Lon protease, thereby stabilizing cellular CLPX levels (www.nature.com). By docking on CLPX, POLDIP2 alters which substrates CLPXP targets for degradation (www.nature.com) (www.nature.com).

One key consequence of POLDIP2 loss is dysregulation of mitochondrial enzyme cofactors. Paredes et al. (2018) discovered that POLDIP2 is required for proper lipoylation of the pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (α-KGDH) complexes (pmc.ncbi.nlm.nih.gov). These multi-enzyme complexes depend on a covalently attached lipoic acid for their activity. In Poldip2-deficient cells, the lipoate ligase LIPT2 and lipoate salvage pathways are intact, but the mitochondrial enzyme ACSM1 (acyl-CoA synthetase medium-chain 1) – which activates exogenous lipoate – becomes abnormally degraded (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Mechanistically, loss of POLDIP2 activates CLPXP to degrade ACSM1, resulting in failure to lipoylate PDH and KGDH E2 subunits (pmc.ncbi.nlm.nih.gov) (www.nature.com). As a result, Poldip2-deficient cells show reduced PDH and α-KGDH activity, a compromised TCA cycle, and lower mitochondrial respiration (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The metabolic fallout includes accumulation of α-ketoglutarate (due to α-KGDH loss) and stabilization of HIF-1α (since α-KG-dependent prolyl hydroxylases are inhibited), linking POLDIP2 loss to a pseudohypoxic, glycolytic shift (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Conversely, overexpression of POLDIP2 increases mitochondrial oxygen consumption and can slow the growth of cancer cells by reinforcing oxidative metabolism (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). POLDIP2 thus acts as a metabolic regulator: it preserves the function of crucial catabolic enzymes by preventing their unwarranted proteolysis.

In line with this role, POLDIP2 expression is responsive to oxygen levels and cancer status. Hypoxia downregulates POLDIP2 in various cell types, and aggressive triple-negative breast cancer cells naturally repress POLDIP2 expression (pmc.ncbi.nlm.nih.gov). This downregulation, while aiding short-term survival under low oxygen, leads to the metabolic inefficiencies noted above. Re-introducing POLDIP2 to these cancer cells restores PDH/α-KGDH lipoylation, raising oxidative metabolism at the expense of proliferative capacity (pmc.ncbi.nlm.nih.gov). These findings highlight POLDIP2 as an oxygen-sensitive metabolic switch (pmc.ncbi.nlm.nih.gov). Consistently, knockout mouse studies underscore the importance of Poldip2 for normal development and cellular homeostasis. Mice completely lacking Poldip2 die perinatally, and their embryonic fibroblasts exhibit reduced growth and elevated autophagy (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Heterozygous Poldip2^+/− mice survive but show extracellular matrix abnormalities (excess, disorganized collagen in blood vessels) and impaired tissue responses to ischemia (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Those phenotypes may result from both metabolic defects and altered cell signaling (as described below). In summary, within mitochondria POLDIP2 serves as a guardian of mitochondrial enzyme integrity and bioenergetic capacity, linking nuclear genetic control to mitochondrial metabolic output.

Role in Redox Signaling, Cytoskeleton, and Vascular Function

POLDIP2 also plays a pivotal role in cellular redox signaling and cytoskeletal dynamics, largely through its interaction with the NADPH oxidase complex. NADPH oxidases (NOX enzymes) are membrane-bound enzymes that generate reactive oxygen species (ROS) as signaling molecules. POLDIP2 was unexpectedly found to bind p22^phox, a membrane subunit essential for multiple NOX isoforms (pmc.ncbi.nlm.nih.gov). In vascular smooth muscle cells, POLDIP2 associates specifically with the NOX4 enzyme – a ROS-producing NADPH oxidase isoform – and markedly increases NOX4 activity (pmc.ncbi.nlm.nih.gov). Overexpression of Poldip2 elevates cellular H_2O_2 production, whereas Poldip2 knockdown reduces basal ROS levels (pmc.ncbi.nlm.nih.gov). POLDIP2, NOX4, and p22^phox co-localize at focal adhesions and along stress fibers in these cells (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Through NOX4, POLDIP2 activation triggers downstream signaling that rearranges the actin cytoskeleton. Specifically, POLDIP2-mediated ROS production activates the small GTPase RhoA and focal adhesion kinase (FAK), master regulators of actin fiber formation and cell migration (pmc.ncbi.nlm.nih.gov). Experimental manipulation of Poldip2 levels dramatically alters cell morphology: increasing Poldip2 boosts RhoA activity, leading to robust actin stress fibers and maturation of focal adhesions, whereas Poldip2 deficiency impairs these structures (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Importantly, these effects depend on the presence of NOX4 and p22^phox – if either NOX4 or its p22^phox subunit is knocked down, Poldip2 can no longer induce RhoA activation or cytoskeletal reorganization (pmc.ncbi.nlm.nih.gov). This indicates POLDIP2 functions as a critical organizer of redox signaling at focal adhesions, linking the NOX4-generated ROS signal to RhoA/FAK pathway activation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The net result is enhanced cell migration capacity, as ROS-mediated focal adhesion turnover is essential for cells to move (pmc.ncbi.nlm.nih.gov).

Through these mechanisms, POLDIP2 helps maintain vascular structure and function. In Poldip2^+/− mice, blood vessels show excess collagen deposition and structural disorganization, correlating with the known role of ROS/RhoA in modulating extracellular matrix remodeling (pmc.ncbi.nlm.nih.gov). Poldip2-haploinsufficient mice also have impaired angiogenesis in response to ischemia (pmc.ncbi.nlm.nih.gov), likely because their vascular cells cannot properly activate ROS-driven migration and remodeling programs. In line with the mouse data, human cardiovascular disease samples have implicated POLDIP2 and NOX4 in pathological remodeling: for instance, patients with chronic pressure-overload heart failure had reduced POLDIP2 and NOX4 in myocardium, suggesting a maladaptive response when this pathway is blunted (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). On the other hand, overactive POLDIP2-NOX4 signaling may contribute to fibrosis: in kidney fibroblast models, POLDIP2 is required for TGF-β to induce NOX4-dependent myofibroblast differentiation and matrix production (www.frontiersin.org) (pmc.ncbi.nlm.nih.gov). Blocking POLDIP2 or NOX4 in such models attenuates the RhoA/ROCK signaling and fibrotic activation (pmc.ncbi.nlm.nih.gov). Thus, POLDIP2 can either support healthy tissue repair or drive pathological remodeling, depending on context.

Besides influencing cell migration and fibrosis, localized POLDIP2/NOX4 activity has been linked to unique signaling processes. One study found POLDIP2, p22^phox, and NOX4 form a complex in renal sensory neurons that modulates mechanosensation. Elevated renal pelvic pressure (a model of fluid back-up in kidneys) increased POLDIP2 expression and its binding to p22^phox, which in turn activated NOX4-derived H_2O_2. The H_2O_2 acted on TRPV1 ion channels in sensory nerve endings to trigger release of substance P, contributing to pain and reflex pathways (www.frontiersin.org) (pmc.ncbi.nlm.nih.gov). This implies POLDIP2 is a component of mechanotransduction signaling via ROS. POLDIP2 has even been observed at the mitotic spindle, though its function there is not yet clear (www.frontiersin.org). One possibility is that its redox-regulatory role might influence spindle dynamics or checkpoint signaling during mitosis, but more research is needed.

In summary, POLDIP2 is a key regulator of ROS signaling and cytoskeletal dynamics. By anchoring and activating NOX4 at strategic locations (focal adhesions, possibly the nucleus (pmc.ncbi.nlm.nih.gov)), it influences processes such as cell migration, adhesion turnover, and extracellular matrix remodeling. These actions are crucial in vascular physiology and pathology – balancing normal vessel maintenance with the potential for fibrosis or aberrant remodeling when dysregulated. POLDIP2 exemplifies how an adaptor protein can couple a redox enzyme to structural and signaling molecules (RhoA/FAK), coordinating biochemical signals with biomechanical outcomes (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Other Biological Roles and Disease Associations

Given its diverse interactions, it is not surprising that POLDIP2 has been implicated in multiple biological pathways and diseases. In the nervous system, recent studies suggest POLDIP2 impacts proteostasis of neuronal proteins. Notably, POLDIP2 has been identified as a novel regulator of Tau protein aggregation in neurodegenerative disease (www.frontiersin.org). Jiang et al. (2015) found that stressors like β-amyloid, TNFα, or oxidative stress upregulate POLDIP2 in neuronal cells, and POLDIP2 overexpression led to impaired autophagy and proteasome function, culminating in accumulation of misfolded Tau and neurotoxic aggregates (www.frontiersin.org) (www.frontiersin.org). In models of Alzheimer’s disease and other tauopathies, elevated POLDIP2 exacerbated Tau aggregation and cell death, whereas knocking down Poldip2 mitigated these effects (www.frontiersin.org). This points to a role for POLDIP2 in protein quality control in neurons – possibly via its influence on oxidative stress or direct binding to regulatory proteins – making it a potential target of interest in neurodegenerative disease research.

In cancer, POLDIP2’s role appears context-dependent. On one hand, POLDIP2’s ability to enforce oxidative metabolism (via mitochondrial function) can suppress the Warburg effect, as seen in breast cancer cells where low POLDIP2 favors glycolysis and rapid growth (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Low POLDIP2 expression has been reported in certain tumors (e.g. triple-negative breast cancers (pmc.ncbi.nlm.nih.gov) and some lung cancers (www.frontiersin.org)), potentially as an adaptation to promote proliferation under stress. Aging-related transcriptome analyses have even flagged POLDIP2 as a risk gene in age-related macular degeneration (AMD), a disease involving oxidative damage in retinal cells (www.aging-us.com). A 2023 study showed that knocking out POLDIP2 in human retinal pigment epithelial cells did not harm cell viability but did trigger a broad antioxidant response: POLDIP2 knockout cells had lower mitochondrial superoxide levels and upregulated the mitochondrial superoxide dismutase (SOD2) (www.aging-us.com). The POLDIP2-deficient RPE cells exhibited changes in immune and complement genes as well (www.aging-us.com), aligning with the idea that POLDIP2 could contribute to oxidative stress and inflammation in AMD. This suggests POLDIP2 could be a modulator of oxidative stress in aging tissues, and by extension, a potential therapeutic target for conditions exacerbated by ROS.

On the other hand, POLDIP2 can also act in a pro-tumor manner under certain conditions. For example, in non-small cell lung cancer (NSCLC), POLDIP2 levels were found to be reduced in patient tumors, yet experimental overexpression of POLDIP2 in NSCLC cell lines paradoxically increased anchorage-independent growth and proliferation (www.frontiersin.org). POLDIP2 overexpression in these cells upregulated Cyclin D1 and mesenchymal markers (N-cadherin, Slug, Twist), promoting an epithelial–mesenchymal transition (EMT) and invasive phenotype (www.frontiersin.org). Conversely, silencing POLDIP2 impaired cell proliferation and EMT marker expression (www.frontiersin.org). These results hint that, at least in some epithelial cancers, residual POLDIP2 may facilitate aggressive traits like anchorage-independent survival and EMT. One possible explanation is that POLDIP2’s ROS/RhoA signaling axis might drive oncogenic pathways (e.g. matrix remodeling and motility for metastasis), even if its metabolic effects are contextually suppressive. Clearly, more research is needed to reconcile POLDIP2’s metabolic tumor-suppressive versus pro-migratory tumor-promoting influences.

In summary, POLDIP2 emerges as a hub protein linking DNA replication, mitochondrial metabolism, and redox signaling. It does so by serving as an adaptor or scaffold for diverse partners – from DNA polymerases in the nucleus to proteases and enzymes in mitochondria to oxidases at the cell membrane. Expert reviewers characterize POLDIP2 as “a multi-functional protein” whose functions “appear to be disparate” yet coordinated by its localization and binding partners (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Because POLDIP2 is unique (no closely related family members) (pmc.ncbi.nlm.nih.gov), it represents a singular point of integration between pathways. Its importance is underscored by the lethal phenotype of Poldip2 knockout in mice (pmc.ncbi.nlm.nih.gov) and its association with diseases ranging from vascular disorders to neurodegeneration and cancer. As of 2023, POLDIP2 is the subject of active research: scientists are investigating it as a potential therapeutic target, for example by modulating POLDIP2-NOX4 signaling to treat fibrosis or targeting POLDIP2’s role in metabolic reprogramming of tumors (www.frontiersin.org). Any intervention, however, must account for the protein’s pleiotropy. For instance, reducing POLDIP2 activity might curb pathological ROS signaling (beneficial in fibrosis or AMD) but could impair DNA repair or mitochondrial function. Conversely, boosting POLDIP2 could improve mitochondrial metabolism in cancer or aging cells but risk promoting ROS-driven damage elsewhere.

Conclusion

In conclusion, Polymerase δ-interacting protein 2 (POLDIP2) is a versatile adaptor protein that operates at critical intersections of cell biology. In the nucleus, it safeguards genome stability by orchestrating DNA polymerase switching during replication stress and repair. In the mitochondrial matrix, it preserves metabolic enzyme function by tempering protease activity, thereby sustaining respiratory capacity. At the cell periphery, it links ROS production to cytoskeletal remodeling, influencing cell migration and tissue architecture. Through these roles, POLDIP2 has a hand in maintaining normal cellular homeostasis and, when dysregulated, contributes to disease processes. Ongoing research (especially from 2020–2024) continues to unravel new facets of POLDIP2 – from its 3D structure and mechanism of action (www.nature.com) (www.nature.com) to its involvement in aging and disease (www.aging-us.com) (www.frontiersin.org). As our understanding deepens, POLDIP2 stands out as an illustrative example of how one protein can integrate signals across cellular compartments, ultimately coordinating DNA-centric processes with energy metabolism and redox signaling. This integrative function makes POLDIP2 a fascinating subject for further study and a potential node for therapeutic intervention in complex diseases.

Sources:

• Liu L. et al., 2003, J. Biol. Chem. – Identification of PDIP38 as a Polδ p50 and PCNA-binding protein (pmc.ncbi.nlm.nih.gov).
• Maga G. et al., 2013, Proc. Natl. Acad. Sci. USA – POLDIP2 enhances Polλ/η-mediated DNA lesion bypass (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
• Guilliam T. et al., 2016, Nucleic Acids Res. – POLDIP2 interacts with PrimPol and aids replication fork restart (www.frontiersin.org).
• Deepa SS et al., 2020, Commun. Biol. – Structural analysis of PDIP38: defined mitochondrial localization and CLPX adaptor function (www.nature.com) (www.nature.com).
• Paredes F. et al., 2018, Proc. Natl. Acad. Sci. USA – POLDIP2 loss impairs PDH/αKGDH via CLPXP, linking POLDIP2 to metabolic reprogramming in hypoxia (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
• Sorrentino et al., 2017, J. Cardiovasc. Pharmacol. – Review: POLDIP2 tissue distribution, roles in DNA repair, mitochondria, focal adhesions; implications in cardiovascular and neuro diseases (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
• Papaharalambus C. et al., 2009, Circ. Res. – Poldip2 identified as a regulator of NOX4, required for ROS production and cytoskeletal integrity in vascular cells (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
• Brown DI et al., 2014, PLoS One – Poldip2 knockout mice: perinatal lethality, smaller embryos, MEFs have growth defect & increased autophagy (pmc.ncbi.nlm.nih.gov).
• Jiang Y. et al., 2015, Biochem. Biophys. Res. Commun. – POLDIP2 overexpression promotes Tau aggregation via autophagy/proteasome impairment (www.frontiersin.org) (www.frontiersin.org).
• Yiu G. et al., 2023, Aging (Albany NY) – CRISPR knockout of POLDIP2 in RPE cells reduces mitochondrial ROS and upregulates antioxidant defenses, linking POLDIP2 to AMD risk (www.aging-us.com) (www.aging-us.com).
• Zhang R. et al., 2022, Front. Med. – Review: POLDIP family roles in disease; summarizes POLDIP2’s interactions (Polδ, PCNA, NOX4, CEACAM1, etc.) and effects in cancers, fibrosis, and neurodegeneration (www.frontiersin.org) (www.frontiersin.org).
• Lin M. et al., 2019, Front. Physiol. – POLDIP2/NOX4 complex in renal mechanosensory signaling (TRPV1 activation under stretch) (www.frontiersin.org).

Citations

1. AnnotationURLCitation(end_index=414, start_index=271, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=Polymerase%20%CE%B4,DNA%20and%20regulate%20its%20expression')
2. AnnotationURLCitation(end_index=581, start_index=415, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=POLDIP2,the%20expression%20level%20of%20POLDIP2')
3. AnnotationURLCitation(end_index=877, start_index=725, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=DNA%20polymerase%20%28Pol%29%20%CE%B4,adhesion%20receptor%20%28%2014')
4. AnnotationURLCitation(end_index=1095, start_index=954, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=The%20polymerase,an%20impaired%20response%20to%20ischemia')
5. AnnotationURLCitation(end_index=1416, start_index=1269, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=almost%20exclusively%20to%20the%20mitochondria,16%20%2C%20%2033')
6. AnnotationURLCitation(end_index=1735, start_index=1592, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=Polymerase%20%CE%B4,DNA%20and%20regulate%20its%20expression')
7. AnnotationURLCitation(end_index=1870, start_index=1736, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=separated%20by%20an%20%CE%B1%2F%CE%B2%20linker,sandwich')
8. AnnotationURLCitation(end_index=2171, start_index=2011, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=binding%20partner%20of%20the%20p50,bacterial%20ApaG%20proteins%20have%20been')
9. AnnotationURLCitation(end_index=2423, start_index=2263, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=binding%20partner%20of%20the%20p50,bacterial%20ApaG%20proteins%20have%20been')
10. AnnotationURLCitation(end_index=2545, start_index=2424, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=match%20at%20L12%20separated%20by,sandwich')
11. AnnotationURLCitation(end_index=2928, start_index=2734, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=match%20at%20L116%20An%20assessment,variety%20of%20binding%20partners%20and')
12. AnnotationURLCitation(end_index=3236, start_index=3062, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=mitochondrial%20targeting%20sequence%20and%20two,bacterial%20ApaG%20proteins%20have%20been')
13. AnnotationURLCitation(end_index=3766, start_index=3615, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=Here%20we%20show%20that%20human,nor%20does%20it%20trigger%20dissociation')
14. AnnotationURLCitation(end_index=3891, start_index=3767, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=clearly%20demonstrate%20that%20the%20PDIP38,K')
15. AnnotationURLCitation(end_index=4231, start_index=4076, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=Poldip2%20contains%20an%20N,molecular%20mass%20of%20the%20mitochondrial')
16. AnnotationURLCitation(end_index=4567, start_index=4416, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=Here%20we%20show%20that%20human,nor%20does%20it%20trigger%20dissociation')
17. AnnotationURLCitation(end_index=4692, start_index=4568, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=clearly%20demonstrate%20that%20the%20PDIP38,K')
18. AnnotationURLCitation(end_index=4959, start_index=4813, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=interaction%20remains%20unknown,adhesion%20receptor%20%28%2014')
19. AnnotationURLCitation(end_index=5108, start_index=4960, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=cells%20or%20HeLa%20cells,is%20consistent%20with%20the%20growing')
20. AnnotationURLCitation(end_index=5384, start_index=5282, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=,Indeed%2C%20over%20the')
21. AnnotationURLCitation(end_index=5709, start_index=5552, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=match%20at%20L299%20Poldip2%20in,19%7D%20Subsequent%20studies%20confirmed')
22. AnnotationURLCitation(end_index=5976, start_index=5866, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=Subcellular%20localization')
23. AnnotationURLCitation(end_index=6147, start_index=5977, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=activity%20of%20the%20Nox4%20enzyme%2C,Poldip2%20levels%20dramatically%20affects%20the')
24. AnnotationURLCitation(end_index=6427, start_index=6312, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=3%20,adhesion%20receptor%20%284')
25. AnnotationURLCitation(end_index=6516, start_index=6428, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=,DOI')
26. AnnotationURLCitation(end_index=6817, start_index=6661, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=the%20mitochondria.,cells%2C%20CEACAM1%20antibody%20clustering%20induces')
27. AnnotationURLCitation(end_index=7143, start_index=6994, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=match%20at%20L191%20It%20may,are%20known%20to%20shuttle%20between')
28. AnnotationURLCitation(end_index=7292, start_index=7144, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=cells%20or%20HeLa%20cells,is%20consistent%20with%20the%20growing')
29. AnnotationURLCitation(end_index=7626, start_index=7478, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=cells%20or%20HeLa%20cells,is%20consistent%20with%20the%20growing')
30. AnnotationURLCitation(end_index=7839, start_index=7684, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=Poldip2%20contains%20an%20N,molecular%20mass%20of%20the%20mitochondrial')
31. AnnotationURLCitation(end_index=8503, start_index=8351, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=DNA%20polymerase%20%28Pol%29%20%CE%B4,adhesion%20receptor%20%28%2014')
32. AnnotationURLCitation(end_index=8754, start_index=8602, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=DNA%20polymerase%20%28Pol%29%20%CE%B4,adhesion%20receptor%20%28%2014')
33. AnnotationURLCitation(end_index=8949, start_index=8755, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=match%20at%20L116%20An%20assessment,variety%20of%20binding%20partners%20and')
34. AnnotationURLCitation(end_index=9457, start_index=9360, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=,Here%2C%20we')
35. AnnotationURLCitation(end_index=9620, start_index=9458, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=match%20at%20L80%20More%20recently%2C,and%20mediating%20the%20switch%20between')
36. AnnotationURLCitation(end_index=9957, start_index=9791, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=More%20recently%2C%20PolDIP2%20has%20been,and%20mediating%20the%20switch%20between')
37. AnnotationURLCitation(end_index=10263, start_index=10109, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=match%20at%20L84%20Pol%20%CE%B7,Pol%20%CE%B7%20and%20the%20replicative')
38. AnnotationURLCitation(end_index=10425, start_index=10264, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=Pol%20%CE%B7%20and%20the%20replicative,Pol%20%CE%B7%20and%20the%20replicative')
39. AnnotationURLCitation(end_index=10707, start_index=10541, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=More%20recently%2C%20PolDIP2%20has%20been,and%20mediating%20the%20switch%20between')
40. AnnotationURLCitation(end_index=11168, start_index=11049, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=Y,and%20its%20effect%20is%20further')
41. AnnotationURLCitation(end_index=11498, start_index=11379, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=Y,and%20its%20effect%20is%20further')
42. AnnotationURLCitation(end_index=11660, start_index=11499, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=evidence%20that%20PolDIP2%20stimulates%20Pol,Finally%2C%20PolDIP2%20silencing')
43. AnnotationURLCitation(end_index=11988, start_index=11827, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=evidence%20that%20PolDIP2%20stimulates%20Pol,Finally%2C%20PolDIP2%20silencing')
44. AnnotationURLCitation(end_index=12108, start_index=11989, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=8,and%20its%20effect%20is%20further')
45. AnnotationURLCitation(end_index=12467, start_index=12310, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=potentiated%20in%20a%20Pol%20%CE%BB,an%20important%20mediator%20for%20TLS')
46. AnnotationURLCitation(end_index=12624, start_index=12468, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=lesion%20by%20both%20Pols%20%CE%B7,an%20important%20mediator%20for%20TLS')
47. AnnotationURLCitation(end_index=13036, start_index=12846, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=POLDIP2%20can%20also%20stimulate%20the,an%20important%20role%20in%20Pol')
48. AnnotationURLCitation(end_index=13228, start_index=13037, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=human%20PrimPol%20and%20enhances%20its,%282016%29%2044%3A3317%E2%80%9329')
49. AnnotationURLCitation(end_index=13556, start_index=13400, title='PolDIP2 interacts with human PrimPol and enhances its DNA polymerase activities | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/44/7/3317/2467854#:~:text=PolDIP2%20interacts%20with%20human%20PrimPol,Specifically%2C%20it%20has')
50. AnnotationURLCitation(end_index=13711, start_index=13557, title='PolDIP2 interacts with human PrimPol and enhances its DNA polymerase activities | Nucleic Acids Research | Oxford Academic', type='url_citation', url='https://academic.oup.com/nar/article/44/7/3317/2467854#:~:text=Depletion%20of%20PolDIP2%20causes%20slowed,Specifically%2C%20it%20has')
51. AnnotationURLCitation(end_index=14212, start_index=14026, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=Liu%20et%20al,involved%20in%20mitochondrial%20function%20modulation')
52. AnnotationURLCitation(end_index=14396, start_index=14213, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=occur%20during%20DNA%20replication%2C%20POLDIP2,G%20TLS%20damage')
53. AnnotationURLCitation(end_index=14720, start_index=14530, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=POLDIP2%20can%20also%20stimulate%20the,an%20important%20role%20in%20Pol')
54. AnnotationURLCitation(end_index=14892, start_index=14721, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=%2822%29,focal%20adhesion%20turnover%20and%20affects')
55. AnnotationURLCitation(end_index=15862, start_index=15741, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=match%20at%20L12%20separated%20by,sandwich')
56. AnnotationURLCitation(end_index=15997, start_index=15863, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=separated%20by%20an%20%CE%B1%2F%CE%B2%20linker,sandwich')
57. AnnotationURLCitation(end_index=16242, start_index=16108, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=separated%20by%20an%20%CE%B1%2F%CE%B2%20linker,sandwich')
58. AnnotationURLCitation(end_index=16523, start_index=16372, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=Here%20we%20show%20that%20human,nor%20does%20it%20trigger%20dissociation')
59. AnnotationURLCitation(end_index=16693, start_index=16524, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=mitochondrial%20PDIP38%20represents%20the%20first,for%20the%20AAA%2B%20protease%2C%20CLPXP')
60. AnnotationURLCitation(end_index=17035, start_index=16878, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=match%20at%20L17%20Importantly%2C%20PDIP38,a%20bona%20fide%20adaptor%20protein')
61. AnnotationURLCitation(end_index=17276, start_index=17119, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=match%20at%20L17%20Importantly%2C%20PDIP38,a%20bona%20fide%20adaptor%20protein')
62. AnnotationURLCitation(end_index=17420, start_index=17277, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=of%20the%20CLPXP%20complex,composed%20of%20two%20domains%2C%20an')
63. AnnotationURLCitation(end_index=17860, start_index=17692, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=Here%2C%20we%20show%20that%20Poldip2,particular%20mammalian%20salvage%20pathway%20of')
64. AnnotationURLCitation(end_index=18359, start_index=18191, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=Here%2C%20we%20show%20that%20Poldip2,particular%20mammalian%20salvage%20pathway%20of')
65. AnnotationURLCitation(end_index=18527, start_index=18360, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=expression%20triggers%20the%20Clp,that%20participates%20in%20metabolic%20adaptation')
66. AnnotationURLCitation(end_index=18823, start_index=18655, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=Here%2C%20we%20show%20that%20Poldip2,particular%20mammalian%20salvage%20pathway%20of')
67. AnnotationURLCitation(end_index=18989, start_index=18824, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=match%20at%20L112%20Nevertheless%2C%20consistent,However%2C%20the%20details%20of%20its')
68. AnnotationURLCitation(end_index=19295, start_index=19127, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=Here%2C%20we%20show%20that%20Poldip2,particular%20mammalian%20salvage%20pathway%20of')
69. AnnotationURLCitation(end_index=19463, start_index=19296, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=expression%20triggers%20the%20Clp,that%20participates%20in%20metabolic%20adaptation')
70. AnnotationURLCitation(end_index=19860, start_index=19693, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=expression%20triggers%20the%20Clp,that%20participates%20in%20metabolic%20adaptation')
71. AnnotationURLCitation(end_index=20031, start_index=19861, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=represses%20mitochondrial%20function,that%20participates%20in%20metabolic%20adaptation')
72. AnnotationURLCitation(end_index=20367, start_index=20194, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=results%20in%20a%20metabolic%20reprogramming,and%20cancer%20cell%20metabolic%20adaptation')
73. AnnotationURLCitation(end_index=20542, start_index=20368, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=complexes%20and%20mitochondrial%20dysfunction,and%20cancer%20cell%20metabolic%20adaptation')
74. AnnotationURLCitation(end_index=21101, start_index=20928, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=results%20in%20a%20metabolic%20reprogramming,and%20cancer%20cell%20metabolic%20adaptation')
75. AnnotationURLCitation(end_index=21534, start_index=21374, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=hypoxia%20in%20a%20variety%20of,and%20cancer%20cell%20metabolic%20adaptation')
76. AnnotationURLCitation(end_index=21786, start_index=21613, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=results%20in%20a%20metabolic%20reprogramming,and%20cancer%20cell%20metabolic%20adaptation')
77. AnnotationURLCitation(end_index=22196, start_index=22042, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=homozygous%20deletion%20of%20Poldip2%20in,of%20this%20study%20was%20to')
78. AnnotationURLCitation(end_index=22288, start_index=22197, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=,Google')
79. AnnotationURLCitation(end_index=22617, start_index=22463, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=homozygous%20deletion%20of%20Poldip2%20in,of%20this%20study%20was%20to')
80. AnnotationURLCitation(end_index=22782, start_index=22618, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=evident%20physiological%20phenotype%2C%20but%20more,of%20this%20study%20was%20to')
81. AnnotationURLCitation(end_index=23680, start_index=23538, title='Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC2744198/#:~:text=smooth%20muscle%20cells%20,hybrid%20screen%20on%20a%20cDNA')
82. AnnotationURLCitation(end_index=24021, start_index=23851, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=activity%20of%20the%20Nox4%20enzyme%2C,Poldip2%20levels%20dramatically%20affects%20the')
83. AnnotationURLCitation(end_index=24307, start_index=24137, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=activity%20of%20the%20Nox4%20enzyme%2C,Poldip2%20levels%20dramatically%20affects%20the')
84. AnnotationURLCitation(end_index=24577, start_index=24407, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=activity%20of%20the%20Nox4%20enzyme%2C,Poldip2%20levels%20dramatically%20affects%20the')
85. AnnotationURLCitation(end_index=24713, start_index=24578, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=p22,Poldip2%20levels%20dramatically%20affects%20the')
86. AnnotationURLCitation(end_index=25143, start_index=24995, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=match%20at%20L352%20p22,phox%7D%2C%20Nox4%20or%20inhibition%20of')
87. AnnotationURLCitation(end_index=25520, start_index=25392, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=p22,phox%7D%2C%20Nox4%20or%20inhibition%20of')
88. AnnotationURLCitation(end_index=25685, start_index=25521, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=match%20at%20L364%20regulates%20Nox4,changes%20required%20for%20cell%20migration')
89. AnnotationURLCitation(end_index=26020, start_index=25892, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=p22,phox%7D%2C%20Nox4%20or%20inhibition%20of')
90. AnnotationURLCitation(end_index=26319, start_index=26191, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=p22,phox%7D%2C%20Nox4%20or%20inhibition%20of')
91. AnnotationURLCitation(end_index=26489, start_index=26320, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=regulates%20Nox4%20and%20its%20downstream,changes%20required%20for%20cell%20migration')
92. AnnotationURLCitation(end_index=26758, start_index=26618, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=depletion%20of%20p22,ones%20dissolving%20at%20the%20rear')
93. AnnotationURLCitation(end_index=27190, start_index=27036, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=homozygous%20deletion%20of%20Poldip2%20in,of%20this%20study%20was%20to')
94. AnnotationURLCitation(end_index=27443, start_index=27279, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=evident%20physiological%20phenotype%2C%20but%20more,of%20this%20study%20was%20to')
95. AnnotationURLCitation(end_index=27982, start_index=27854, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=match%20at%20L432%20accompanied%20by,induced')
96. AnnotationURLCitation(end_index=28111, start_index=27983, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=accompanied%20by%20a%20decrease%20in,induced')
97. AnnotationURLCitation(end_index=28536, start_index=28334, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=subsequently%20result%20in%20Tau%20aggregation,in%20the%20pathogenesis%20of%20renal')
98. AnnotationURLCitation(end_index=28699, start_index=28537, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=the%20experimental%20evidence%20that%20Poldip2,induced%20Nox4%20activity%20and')
99. AnnotationURLCitation(end_index=28962, start_index=28800, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=the%20experimental%20evidence%20that%20Poldip2,induced%20Nox4%20activity%20and')
100. AnnotationURLCitation(end_index=29863, start_index=29637, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=RhoA%2FRock%2FPOLDIP2%2FNOX4%2FROS%20pathway%20can%20induce%20the,mediated%20mechanosensation.%20Using%20co')
101. AnnotationURLCitation(end_index=30008, start_index=29864, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=the%20activity%20of%20renal%20transient,phox%7D%20in%20renal')
102. AnnotationURLCitation(end_index=30345, start_index=30190, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=subcellular%20localizations,4%2C%205')
103. AnnotationURLCitation(end_index=30850, start_index=30682, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=As%20described%20below%2C%20Poldip2%20can,own%20signaling%20functions%20might%20have')
104. AnnotationURLCitation(end_index=31440, start_index=31312, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=p22,phox%7D%2C%20Nox4%20or%20inhibition%20of')
105. AnnotationURLCitation(end_index=31605, start_index=31441, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=match%20at%20L364%20regulates%20Nox4,changes%20required%20for%20cell%20migration')
106. AnnotationURLCitation(end_index=32216, start_index=32012, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=regulator%20of%20Tau%20aggregation%20in,and%20partially%20proteasome%20activity%20and')
107. AnnotationURLCitation(end_index=32698, start_index=32494, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=regulator%20of%20Tau%20aggregation%20in,and%20partially%20proteasome%20activity%20and')
108. AnnotationURLCitation(end_index=32893, start_index=32699, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=stroke%20mortality%20%2829%29,Tau%20aggregation%20without%20affecting%20Tau')
109. AnnotationURLCitation(end_index=33260, start_index=33066, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=stroke%20mortality%20%2829%29,Tau%20aggregation%20without%20affecting%20Tau')
110. AnnotationURLCitation(end_index=33946, start_index=33773, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=results%20in%20a%20metabolic%20reprogramming,and%20cancer%20cell%20metabolic%20adaptation')
111. AnnotationURLCitation(end_index=34121, start_index=33947, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=complexes%20and%20mitochondrial%20dysfunction,and%20cancer%20cell%20metabolic%20adaptation')
112. AnnotationURLCitation(end_index=34392, start_index=34219, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=results%20in%20a%20metabolic%20reprogramming,and%20cancer%20cell%20metabolic%20adaptation')
113. AnnotationURLCitation(end_index=34602, start_index=34415, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=match%20at%20L160%20hydroxylase,shown%20in%20the%20mechanism%20study')
114. AnnotationURLCitation(end_index=35035, start_index=34854, title='Knockout of AMD-associated gene POLDIP2 reduces mitochondrial superoxide in human retinal pigment epithelial cells | Aging', type='url_citation', url='https://www.aging-us.com/article/204522/text#:~:text=highlighted%20POLDIP2%20as%20a%20significant,immune%20response%2C%20complement%20activation%2C%20oxidative')
115. AnnotationURLCitation(end_index=35484, start_index=35330, title='Knockout of AMD-associated gene POLDIP2 reduces mitochondrial superoxide in human retinal pigment epithelial cells | Aging', type='url_citation', url='https://www.aging-us.com/article/204522/text#:~:text=changes%20in%20genes%20involved%20in,regulating%20oxidative%20stress%20in%20AMD')
116. AnnotationURLCitation(end_index=35712, start_index=35575, title='Knockout of AMD-associated gene POLDIP2 reduces mitochondrial superoxide in human retinal pigment epithelial cells | Aging', type='url_citation', url='https://www.aging-us.com/article/204522/text#:~:text=generation%20of%20a%20stable%20human,In%20conclusion%2C%20this')
117. AnnotationURLCitation(end_index=36515, start_index=36323, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=NSCLC%20tissues%2C%20and%20the%20overexpressed,EMT%29%20markers%2C%20cdh2')
118. AnnotationURLCitation(end_index=36896, start_index=36704, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=NSCLC%20tissues%2C%20and%20the%20overexpressed,EMT%29%20markers%2C%20cdh2')
119. AnnotationURLCitation(end_index=37174, start_index=36982, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=NSCLC%20tissues%2C%20and%20the%20overexpressed,EMT%29%20markers%2C%20cdh2')
120. AnnotationURLCitation(end_index=38322, start_index=38156, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=Polymerase%20%CE%B4,Poldip2%20in%20cardiovascular%20disease%2C%20neurodegenerative')
121. AnnotationURLCitation(end_index=38472, start_index=38323, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=match%20at%20L191%20It%20may,are%20known%20to%20shuttle%20between')
122. AnnotationURLCitation(end_index=38710, start_index=38536, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=match%20at%20L210%20subcellular%20compartments,performing%20functions%20that%20cannot%20be')
123. AnnotationURLCitation(end_index=39012, start_index=38858, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=homozygous%20deletion%20of%20Poldip2%20in,of%20this%20study%20was%20to')
124. AnnotationURLCitation(end_index=39546, start_index=39370, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=instance%2C%20adenoviral,specific%20POLDIPs%20restoration')
125. AnnotationURLCitation(end_index=40900, start_index=40766, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=separated%20by%20an%20%CE%B1%2F%CE%B2%20linker,sandwich')
126. AnnotationURLCitation(end_index=41044, start_index=40901, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=of%20the%20CLPXP%20complex,composed%20of%20two%20domains%2C%20an')
127. AnnotationURLCitation(end_index=41239, start_index=41085, title='Knockout of AMD-associated gene POLDIP2 reduces mitochondrial superoxide in human retinal pigment epithelial cells | Aging', type='url_citation', url='https://www.aging-us.com/article/204522/text#:~:text=changes%20in%20genes%20involved%20in,regulating%20oxidative%20stress%20in%20AMD')
128. AnnotationURLCitation(end_index=41432, start_index=41240, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=NSCLC%20tissues%2C%20and%20the%20overexpressed,EMT%29%20markers%2C%20cdh2')
129. AnnotationURLCitation(end_index=42101, start_index=41949, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=DNA%20polymerase%20%28Pol%29%20%CE%B4,adhesion%20receptor%20%28%2014')
130. AnnotationURLCitation(end_index=42336, start_index=42217, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=Y,and%20its%20effect%20is%20further')
131. AnnotationURLCitation(end_index=42493, start_index=42337, title='DNA polymerase δ-interacting protein 2 is a processivity factor for DNA polymerase λ during 8-oxo-7,8-dihydroguanine bypass - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC3839753/#:~:text=lesion%20by%20both%20Pols%20%CE%B7,an%20important%20mediator%20for%20TLS')
132. AnnotationURLCitation(end_index=42809, start_index=42619, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=POLDIP2%20can%20also%20stimulate%20the,an%20important%20role%20in%20Pol')
133. AnnotationURLCitation(end_index=43088, start_index=42954, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=separated%20by%20an%20%CE%B1%2F%CE%B2%20linker,sandwich')
134. AnnotationURLCitation(end_index=43246, start_index=43089, title='Polymerase delta-interacting protein 38 (PDIP38) modulates the stability and activity of the mitochondrial AAA+ protease CLPXP | Communications Biology', type='url_citation', url='https://www.nature.com/articles/s42003-020-01358-6#:~:text=match%20at%20L17%20Importantly%2C%20PDIP38,a%20bona%20fide%20adaptor%20protein')
135. AnnotationURLCitation(end_index=43578, start_index=43410, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=Here%2C%20we%20show%20that%20Poldip2,particular%20mammalian%20salvage%20pathway%20of')
136. AnnotationURLCitation(end_index=43749, start_index=43579, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=represses%20mitochondrial%20function,that%20participates%20in%20metabolic%20adaptation')
137. AnnotationURLCitation(end_index=44123, start_index=43957, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=Polymerase%20%CE%B4,Poldip2%20in%20cardiovascular%20disease%2C%20neurodegenerative')
138. AnnotationURLCitation(end_index=44252, start_index=44124, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=p22,phox%7D%2C%20Nox4%20or%20inhibition%20of')
139. AnnotationURLCitation(end_index=44597, start_index=44427, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=activity%20of%20the%20Nox4%20enzyme%2C,Poldip2%20levels%20dramatically%20affects%20the')
140. AnnotationURLCitation(end_index=44726, start_index=44598, title='Polymerase δ-interacting protein 2: a multifunctional protein - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5556945/#:~:text=p22,phox%7D%2C%20Nox4%20or%20inhibition%20of')
141. AnnotationURLCitation(end_index=44972, start_index=44881, title='Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5828627/#:~:text=,Google')
142. AnnotationURLCitation(end_index=45330, start_index=45126, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=regulator%20of%20Tau%20aggregation%20in,and%20partially%20proteasome%20activity%20and')
143. AnnotationURLCitation(end_index=45525, start_index=45331, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=stroke%20mortality%20%2829%29,Tau%20aggregation%20without%20affecting%20Tau')
144. AnnotationURLCitation(end_index=45866, start_index=45712, title='Knockout of AMD-associated gene POLDIP2 reduces mitochondrial superoxide in human retinal pigment epithelial cells | Aging', type='url_citation', url='https://www.aging-us.com/article/204522/text#:~:text=changes%20in%20genes%20involved%20in,regulating%20oxidative%20stress%20in%20AMD')
145. AnnotationURLCitation(end_index=46025, start_index=45867, title='Knockout of AMD-associated gene POLDIP2 reduces mitochondrial superoxide in human retinal pigment epithelial cells | Aging', type='url_citation', url='https://www.aging-us.com/article/204522/text#:~:text=highlighted%20POLDIP2%20as%20a%20significant,19%20with%20POLDIP2%20knockout%20using')
146. AnnotationURLCitation(end_index=46395, start_index=46240, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=subcellular%20localizations,4%2C%205')
147. AnnotationURLCitation(end_index=46585, start_index=46396, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=immunoprecipitation%20experiments%2C%20they%20have%20demonstrated,NOX4')
148. AnnotationURLCitation(end_index=46952, start_index=46726, title='Frontiers | The polymerase δ-interacting protein family and their emerging roles in diseases', type='url_citation', url='https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1026931/full#:~:text=RhoA%2FRock%2FPOLDIP2%2FNOX4%2FROS%20pathway%20can%20induce%20the,mediated%20mechanosensation.%20Using%20co')