POLE4 (DNA Polymerase Epsilon Subunit 4) – Function, Processes, and Localization

Overview:
POLE4 (UniProt ID Q9NR33) encodes the smallest accessory subunit of DNA polymerase epsilon (Pol ε) in humans (www.abcam.com). Pol ε is a tetrameric enzyme complex and one of the core replicative DNA polymerases responsible for leading-strand DNA synthesis during S-phase (pmc.ncbi.nlm.nih.gov). The Pol ε holoenzyme consists of a large catalytic subunit (POLE, also called POLE1) with DNA polymerase and exonuclease (proofreading) activities, a second subunit (POLE2) that links Pol ε to the CMG helicase, and two small accessory subunits, POLE3 and POLE4, which lack catalytic activity but play critical structural and regulatory roles (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). POLE4 is also known as the p12 subunit of Pol ε (reflecting its ~12 kDa size) and has been identified in other nuclear complexes (historically termed CHRAC15 in the chromatin accessibility complex) due to its unique structural motif (pmc.ncbi.nlm.nih.gov) (www.abcam.com). Crucially, POLE4 functions within the nucleus at DNA replication forks, where it supports high-fidelity DNA replication and coordinates chromatin assembly, as detailed below.

Structural Features and Complex Assembly

POLE4 is a histone-fold protein, meaning it contains a helix-loop-helix motif structurally analogous to histone proteins. The C-terminal region of POLE4 adopts an H2A-like histone fold, while its partner POLE3 provides an H2B-like histone fold (pmc.ncbi.nlm.nih.gov). These two subunits form a stable POLE3–POLE4 heterodimer via conserved hydrophobic interactions (analogous to the H2A–H2B dimer in nucleosomes) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Biochemical reconstitution experiments have confirmed that human POLE3 and POLE4 directly bind each other to form a tight complex, remaining associated even in high-salt conditions (pmc.ncbi.nlm.nih.gov). This heterodimer interfaces with the Pol ε holoenzyme: POLE3–POLE4 docks onto the catalytic subunit (POLE1), enhancing the stability and DNA-binding capacity of the polymerase complex (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Indeed, structural modeling shows the POLE3–POLE4 dimer superimposes closely with the crystal structure of the yeast Pol ε small-subunit complex (Dpb3–Dpb4) (pmc.ncbi.nlm.nih.gov), highlighting the evolutionary conservation of this assembly.

Complex Stability: In higher eukaryotes, POLE4 is critical for maintaining Pol ε complex integrity. A targeted mouse knockout of Pole4 demonstrated that without POLE4, the entire Pol ε complex becomes destabilized, leading to greatly reduced levels of the other subunits (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Pole4^−/−^ mouse embryonic fibroblasts show loss of POLE3 and marked reduction of POLE1/POLE2 protein levels, indicating that POLE3–POLE4 normally stabilize the catalytic core (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Consistently, human cell studies have found that depleting POLE4 triggers co-depletion of POLE3, implying the two exist as an interdependent subcomplex in vivo (pmc.ncbi.nlm.nih.gov). In budding yeast (S. cerevisiae), the homologous small subunits (Dpb3 and Dpb4) are not essential for viability, and Pol ε can assemble without them (pmc.ncbi.nlm.nih.gov). However, the dispensability in yeast is likely due to compensatory mechanisms, as yeast Pol ε lacking Dpb3/4 shows reduced DNA-binding processivity in vitro (pmc.ncbi.nlm.nih.gov) and increased mutation rates in vivo (pmc.ncbi.nlm.nih.gov). In mammals, by contrast, POLE4 is required for normal development – loss of POLE4 in mice causes embryonic lethality on certain genetic backgrounds and severe growth defects with genomic instability in survivors (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This highlights that POLE4’s stabilizing role became crucial in higher eukaryotes, likely due to added demands on replication fidelity and genome maintenance.

Function in DNA Replication

Pol ε’s primary function is high-fidelity DNA synthesis on the leading strand of the replication fork. The POLE catalytic subunit polymerizes nucleotides in the 5′→3′ direction, with an intrinsic 3′→5′ exonuclease activity for proofreading errors. While POLE4 itself does not catalyze DNA synthesis, it contributes to the efficiency and regulation of replication through its role in the Pol ε complex. Pol ε is considered the major leading-strand DNA polymerase in eukaryotes (pmc.ncbi.nlm.nih.gov), working in concert with the replisome (the CMG helicase, primase, clamp loader, etc.) to duplicate the genome each S-phase. Importantly, emerging evidence shows that Pol ε has multiple, stage-specific roles in replication beyond just nucleotide incorporation:

• Replication Initiation: Pol ε is required to initiate leading-strand synthesis and is also involved in origin firing. The non-catalytic N-terminal domains of Pol ε (on POLE1/POLE2) help assemble the active CMG helicase at origins and trigger origin activation (pmc.ncbi.nlm.nih.gov). Even if the polymerase activity of Pol ε is experimentally bypassed, these assembly functions are essential for viability (pmc.ncbi.nlm.nih.gov). POLE4, by stabilizing Pol ε, indirectly supports this process; without POLE4, cells have inefficient replication origin firing and must rely on fewer active forks (pmc.ncbi.nlm.nih.gov). Pole4-deficient mouse cells showed abnormally large inter-origin distances, indicative of fewer active origins, and a compensatory increase in fork speed at remaining forks (pmc.ncbi.nlm.nih.gov). This suggests that a fully intact Pol ε (including POLE4) is needed for proper origin density and replication timing.

• Polymerase Processivity and Fork Progression: The POLE3/POLE4 subunits are thought to enhance Pol ε’s ability to remain engaged with DNA. Early studies in yeast demonstrated that a Pol ε lacking Dpb3/4 synthesizes DNA with lower processivity (falling off the template more readily) (pmc.ncbi.nlm.nih.gov). The histone-fold dimer of POLE3–POLE4 can bind double-stranded DNA in a sequence-independent manner, much like histone proteins binding DNA (www.ncbi.nlm.nih.gov). This binding may serve to tether Pol ε to the newly synthesized duplex behind the fork, thereby supporting continuous, processive replication (pmc.ncbi.nlm.nih.gov). (Notably, one study reconstituting human Pol ε found that removing POLE3/4 had little effect on polymerization rate in vitro, hinting that their functions in higher eukaryotes might be specialized beyond simple rate enhancement (pmc.ncbi.nlm.nih.gov).) In vivo, however, loss of POLE4 clearly slows replication fork progression. A recent 2024 study reported that POLE4-knockout human cells exhibit reduced fork speed and altered replication dynamics (pubmed.ncbi.nlm.nih.gov) (academic.oup.com). The absence of POLE3/4 led to replication stress markers despite normal checkpoint activation, underscoring that these subunits are needed for optimal fork movement and completion (pubmed.ncbi.nlm.nih.gov).

• Coordination with the Replisome: Pol ε also acts as a structural hub at the fork. It physically links with the Ctf18-RFC clamp loader complex, which helps load PCNA clamps during replication and is involved in establishing sister chromatid cohesion (pmc.ncbi.nlm.nih.gov). The Pol ε complex (likely via POLE2 or associated domains) attaches the Ctf18 complex to the replisome, supporting processive DNA synthesis and proper cohesion of sister chromatids (pmc.ncbi.nlm.nih.gov). While this role is primarily attributed to Pol ε’s larger subunits, the entire complex’s stability (which depends on POLE4) is necessary to maintain such interactions. Therefore, POLE4 indirectly contributes to sister chromatid cohesion and genome stability by keeping Pol ε anchored in the replisome architecture (pmc.ncbi.nlm.nih.gov).

High-Fidelity DNA Synthesis: Through the above mechanisms, Pol ε (with POLE4 as part of the complex) ensures that leading-strand DNA is replicated accurately and efficiently. POLE4’s importance is evident in how its loss increases replication errors and genome instability. Yeast lacking Dpb3/4 show elevated spontaneous mutagenesis (pmc.ncbi.nlm.nih.gov), and in mice, Pole4 deficiency triggers p53-dependent stress responses due to replication difficulties (pmc.ncbi.nlm.nih.gov). Thus, while POLE4 does not catalyze nucleotide addition, it guards replication fidelity by stabilizing Pol ε and preventing replication slippage or fork collapse.

Role in Chromatin Assembly and Genome Maintenance

Beyond polymerization, POLE4 plays a key role in coupling DNA replication with chromatin assembly. This has emerged as a critical function of the POLE3–POLE4 subcomplex in higher eukaryotes (pmc.ncbi.nlm.nih.gov). As the replication fork progresses, parental nucleosomes are disassembled ahead of the fork and new nucleosomes must form promptly behind the fork to restore chromatin structure and preserve epigenetic information (pmc.ncbi.nlm.nih.gov). Several lines of evidence indicate POLE4 is directly involved in this replication-coupled nucleosome assembly process:

• Histone Chaperone Activity: In 2018, Bellelli et al. demonstrated that the POLE3–POLE4 dimer functions as a bona fide histone chaperone for H3–H4 histones (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Using purified proteins, they showed POLE3–POLE4 can bind core histones H3–H4 in vitro and facilitate the formation of tetrasomes (a DNA–H3/H4 intermediate in nucleosome assembly) accompanied by DNA supercoiling (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This is a hallmark of histone chaperone activity. The complex binds H3–H4 both in vitro and in vivo, indicating that POLE4 (with POLE3) escorts histone complexes during replication (pmc.ncbi.nlm.nih.gov). Notably, the histone-binding function was mapped to the C-terminus of POLE3 (which interacts with H3–H4), and mutations that disrupt the POLE3–POLE4 heterodimer also abolish histone binding (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This firmly establishes that POLE4 is part of a replisome-associated histone H3–H4 chaperone complex.

• Parental Histone Recycling: POLE4’s contribution to chromatin was foreshadowed by yeast studies. Deletion of Dpb3/Dpb4 in yeast causes defects in heterochromatin maintenance at telomeres and other regions (pmc.ncbi.nlm.nih.gov). Dpb3/Dpb4 mutants phenocopy mutations in known chromatin assembly factors (like CAF-1 and Asf1) with respect to losing transcriptional gene silencing at heterochromatic loci (pmc.ncbi.nlm.nih.gov). These observations suggested the small Pol ε subunits aid in redepositing parental histones onto daughter DNA strands, thereby preserving epigenetic marks (pmc.ncbi.nlm.nih.gov). The Bellelli et al. study confirmed this in mammalian cells: POLE3/POLE4 depletion leads to defective nucleosome re-assembly at forks, evidenced by abnormalities in replication-fork chromatin. Specifically, cells lacking POLE3/4 showed aberrant RPA accumulation and prolonged PCNA retention on chromatin, indicative of unprocessed single-stranded DNA and delayed maturation of newly replicated chromatin (pmc.ncbi.nlm.nih.gov). In normal cells, as new nucleosomes form, RPA (which binds single-stranded DNA) is displaced and PCNA (the sliding clamp) eventually unloads once Okazaki fragments are ligated and chromatin is in place. The persistence of RPA and PCNA in POLE4-deficient cells points to problems in chromatin reassembly behind the fork (pmc.ncbi.nlm.nih.gov). Thus, POLE4 is required for timely restoration of chromatin structure during replication, working in concert with other histone chaperones.

• Genome Stability and DNA Repair: By ensuring proper chromatin assembly, POLE4 helps maintain genome stability. In the absence of POLE3/4, newly replicated DNA is more prone to damage and irregularities. For example, loss of POLE4 triggers a DNA damage-like response: ATR (ATM and Rad3-related kinase) signaling is elevated, and p53 is activated due to replication stress (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). A 2024 study showed that POLE4 knockout cells accumulate post-replicative single-strand DNA gaps – stretches of unreplicated or unligated DNA left behind replication forks (pubmed.ncbi.nlm.nih.gov). These gaps are normally repaired or filled in by post-replication repair pathways; however, POLE4-deficient cells exhibit impaired processing of such gaps, especially under stress conditions (pubmed.ncbi.nlm.nih.gov). Consequently, when treated with PARP inhibitors (which block a DNA single-strand break repair pathway), POLE4-null cells suffer catastrophic levels of DNA gaps and breaks, leading to hypersensitivity to the drug (pubmed.ncbi.nlm.nih.gov). This finding underscores POLE4’s role in facilitating the completion of DNA replication and repair of any residual nicks or gaps, likely by coordinating with repair polymerases or ligases after the replication fork has passed. Additionally, cells lacking POLE3/4 show heightened ATR checkpoint signaling and activation of DNA-PK (a kinase in double-strand break repair), consistent with the accumulation of replication-associated DNA lesions (pubmed.ncbi.nlm.nih.gov). Altogether, these data indicate that POLE4 is crucial for preventing replication stress – it helps Pol ε synthesize DNA continuously and couples that synthesis to immediate chromatin restoration, thereby avoiding abnormal single-stranded regions or DNA damage during S-phase.

It is worth noting that while Pol ε’s primary task is replication, it can also participate in certain DNA repair processes. Pol ε contributes to nucleotide excision repair and long-patch base-excision repair in some contexts, and its exonuclease activity can aid mismatch repair, although Pol δ plays the dominant role in the latter. POLE4’s direct involvement in repair is less well-characterized, but by similarity to yeast and other systems, Pol ε’s accessory subunits are thought to assist in repair-related DNA synthesis and nucleosome reassembly following repair (www.abcam.com) (www.ncbi.nlm.nih.gov). In summary, POLE4’s maintenance of Pol ε integrity and its histone chaperoning function combine to safeguard the genome during both DNA replication and the maturation of replicated DNA.

Cellular Localization and Context of Action

Subcellular localization: The POLE4 protein carries out its functions in the cell nucleus, in line with its role at replication forks. Immunocytochemistry and protein localization data confirm that POLE4 is predominantly found in the nucleoplasm (the interior nuclear space where DNA replication occurs) (www.proteinatlas.org). During S-phase, POLE4 localizes to replication foci – discrete nuclear sites of active DNA synthesis – as part of the Pol ε complex. Some studies and proteomic data have also detected a fraction of POLE4 in the cytosol (www.proteinatlas.org), but this likely represents unassembled protein or pre-import pools, since the functional action of POLE4 requires it to be in the nucleus and incorporated into Pol ε or other chromatin complexes. There is no signal peptide or transmembrane domain in POLE4 (v23.proteinatlas.org), and it is predicted to be an intracellular protein, consistent with a nuclear/chromatin role. Thus, inside the cell nucleus is the principal site of POLE4 activity, specifically at the replication machinery and chromatin interface.

Complex associations: Within the nucleus, POLE4 exists in at least two major complexes: (1) the Pol ε holoenzyme at replication forks, and (2) the CHRAC (Chromatin Accessibility Complex) involved in chromatin remodeling. The human CHRAC complex, which facilitates nucleosome spacing and chromatin assembly, contains the ATP-dependent remodeler ACF1 and two small histone-fold proteins originally termed CHRAC17 and CHRAC15 (pmc.ncbi.nlm.nih.gov). Notably, CHRAC17 is identical to POLE3, and CHRAC15 is the POLE4 protein (pmc.ncbi.nlm.nih.gov). In other words, POLE3–POLE4 double as subunits in a chromatin remodeling complex, reflecting their ability to bind DNA and histones. This dual presence suggests that POLE4 is not only integral to the replication fork, but also contributes to broader chromatin metabolism. In the CHRAC context, POLE3/POLE4 help the ISWI-family remodeler to organize nucleosomes and modulate DNA accessibility (pmc.ncbi.nlm.nih.gov). The interchangeable use of POLE4 in both replication and remodeling complexes underlines its general role as a DNA-binding adapter that can be recruited to different machinery where a histone-fold module is needed.

Pathway Integration and Biological Impact

Replication and Cell Cycle Pathways: POLE4 functions within the core DNA replication pathway, particularly the leading-strand synthesis arm of the eukaryotic replisome. Through Pol ε, it is connected to the cell cycle regulation of S-phase. For instance, proper Pol ε assembly (including POLE4) is required for the activation of replication origins in concert with S-phase kinase signaling (pmc.ncbi.nlm.nih.gov). If POLE4 or Pol ε is defective, intra-S phase checkpoints (like ATR) are activated due to replication stress (pubmed.ncbi.nlm.nih.gov). Indeed, Pol ε has been proposed to serve as a sensor in the S-phase DNA damage checkpoint, since stalls in leading strand synthesis rapidly trigger ATR/Chk1 signaling. Some of this sensing function is attributed to the large subunit (POLE1) and its interaction with checkpoint proteins, but maintaining Pol ε’s presence via POLE4 is necessary for these signals to be effective (pmc.ncbi.nlm.nih.gov). Therefore, POLE4 indirectly partakes in the DNA damage response (DDR) pathways: by preventing replication fork collapse it reduces the need for checkpoint activation, and when problems occur, a Pol ε complex with POLE4 can properly signal and recruit repair machinery (pmc.ncbi.nlm.nih.gov). The 2022 mini-review by Cvetkovic et al. encapsulates Pol ε’s multi-faceted roles, noting that Pol ε “supports processive DNA synthesis, DNA damage response signaling as well as sister chromatid cohesion” as part of its structural functions at the fork (pmc.ncbi.nlm.nih.gov). POLE4 is an essential contributor to these outcomes.

Development and Disease: The importance of POLE4 for normal cell physiology is evident from genetic studies. In vivo, knockout of Pole4 in mice is lethal on certain backgrounds or causes severe developmental abnormalities (pmc.ncbi.nlm.nih.gov). Pole4^−/−^ embryos that survive exhibit growth retardation, immune cell deficiencies (leukopenia), and a high incidence of developmental defects (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Many of these phenotypes (growth impairment, immunodeficiency) resemble those seen in human patients with hypomorphic mutations in POLE1/POLE2 (pmc.ncbi.nlm.nih.gov), underlining that a functional Pol ε complex is required for proliferative tissues and genome maintenance in mammals. The developmental arrest and cell death in Pole4-null conditions are largely due to unresolved replication stress activating p53-mediated apoptosis (pmc.ncbi.nlm.nih.gov). When p53 was removed in Pole4-deficient mice, viability improved, but these animals developed cancers at an accelerated rate (pmc.ncbi.nlm.nih.gov). This reveals that POLE4 has a tumor suppressor role via maintaining replication fidelity – in its absence, cells accumulate DNA errors and genomic instability that predispose to cancer (unless eliminated by p53-driven checkpoints) (pmc.ncbi.nlm.nih.gov).

In the context of human disease, POLE4 itself is not a well-known mutational hotspot (unlike POLE, whose exonuclease-domain mutations cause ultramutator tumors). However, the POLE3–POLE4 subunits have attracted interest as possible targets for therapy. Because cells lacking these subunits are vulnerable to PARP inhibitors, researchers suggest that inhibiting the POLE3–POLE4 function could be a strategy to induce lethal replication stress in cancer cells (pubmed.ncbi.nlm.nih.gov). A June 2024 Nucleic Acids Research study by Mamar et al. showed that removing POLE4 in cancer cells synergizes with PARP inhibition, even in tumors that are BRCA1-proficient (pubmed.ncbi.nlm.nih.gov). The loss of POLE4 slows DNA replication and leads to accumulation of single-stranded gaps, which PARP inhibitors convert into fatal DNA damage (pubmed.ncbi.nlm.nih.gov). Thus, POLE4 is emerging as a potential target to exploit replication stress in cancer therapy (pubmed.ncbi.nlm.nih.gov). These findings, while translational, reinforce the notion that POLE4’s normal role is to prevent pathological replication stress by aiding complete DNA synthesis and chromatin maturation.

Summary of Key Points

• Primary Function: POLE4 is a non-enzymatic subunit of DNA polymerase ε, essential for leading-strand DNA replication. It does not catalyze DNA synthesis itself, but it enables the Pol ε complex to function properly. The Pol ε enzyme (with POLE4 as a component) catalyzes the polymerization of deoxynucleotides onto the growing DNA strand with high fidelity, and includes proofreading capability in the POLE1 subunit (pmc.ncbi.nlm.nih.gov). POLE4’s broader role is structural and regulatory – it stabilizes the polymerase and connects it to DNA and chromatin substrates.

• Molecular Mechanism: POLE4 contains a histone-fold domain and forms a heterodimer with POLE3 (pmc.ncbi.nlm.nih.gov). This POLE3–POLE4 pair binds double-stranded DNA without sequence specificity (www.ncbi.nlm.nih.gov) and associates with histones H3–H4 (pmc.ncbi.nlm.nih.gov). Through these interactions, POLE4 increases Pol ε’s binding to DNA and promotes nucleosome reassembly behind the replication fork (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). It effectively acts as an adapter/chaperone, bridging the replication machinery with chromatin.

• Biological Processes: POLE4 is involved in chromosomal DNA replication – specifically initiation of replication (origin firing) and elongation on the leading strand (pmc.ncbi.nlm.nih.gov). It is also critical for replication-coupled nucleosome assembly, helping recycle parental histones and deposit new histones to maintain chromatin integrity (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). By ensuring proper chromatin restoration, POLE4 aids in preserving epigenetic information and heterochromatin structures during replication (pmc.ncbi.nlm.nih.gov). Additionally, POLE4 contributes to the cellular DNA damage response to stalled forks and influences post-replicative repair of DNA gaps (pubmed.ncbi.nlm.nih.gov). It thereby plays a role in maintaining overall genome stability during cell proliferation.

• Cellular Localization: The POLE4 protein functions in the nucleus, predominantly in the nucleoplasm and at sites of DNA replication (replication foci) (www.proteinatlas.org). It is a component of nuclear enzymatic complexes (Pol ε and CHRAC) and is not secreted or membrane-bound. A minor cytosolic presence may occur, but active POLE4 is nuclear, where it associates with DNA, histones, and replication factories (www.abcam.com).

• Pathway and Interactions: POLE4 operates within the DNA replication pathway and S-phase checkpoint network. It is required for proper assembly of the CMG helicase and the progression of replication forks (pmc.ncbi.nlm.nih.gov). It also has a role in linking the replication fork to chromatin cohesion mechanisms via the Ctf18 clamp loader (pmc.ncbi.nlm.nih.gov). In terms of signaling, a functional Pol ε (with POLE4 intact) is needed for normal ATR-dependent checkpoint activation when replication stress occurs (pmc.ncbi.nlm.nih.gov). Loss of POLE4 skews this balance, leading to heightened ATR signaling and reliance on p53 to halt the cell cycle (pmc.ncbi.nlm.nih.gov).

All these findings are supported by recent experimental evidence. For example, Bellelli et al. (2018) showed biochemically that POLE3–POLE4 binds histones and is required for nucleosome assembly during replication (pmc.ncbi.nlm.nih.gov). Cox et al. (2018) demonstrated in a Pole4^-/- mouse model that POLE4 is indispensable for Pol ε stability and normal development (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Mamar et al. (NAR, 2024) and Hill et al. (Cell Rep, 2024) independently found that cells lacking POLE4 experience slower replication and accumulate ssDNA gaps, linking POLE4 to replication-fork repair processes (pubmed.ncbi.nlm.nih.gov). Furthermore, a 2022 review by Bellelli and colleagues summarizes that Pol ε’s histone-fold subunits (POLE3/4), while not essential for the polymerase activity per se, serve a critical role in redepositing parental histones onto newly synthesized DNA and supporting fork progression (pmc.ncbi.nlm.nih.gov). These authoritative sources collectively portray POLE4 as a key adapter protein that connects the enzymatic function of DNA polymerase ε to the structural demands of chromatin replication, thereby ensuring that DNA duplication and nucleosome assembly proceed hand-in-hand.

References: Recent research and reviews were used to compile this information, including Molecular Cell (2018) (pmc.ncbi.nlm.nih.gov), Cell Reports (2018) (pmc.ncbi.nlm.nih.gov), Biochemical Society Transactions (2022) (pmc.ncbi.nlm.nih.gov), and Nucleic Acids Research (2024) (pubmed.ncbi.nlm.nih.gov), among others. These studies provide experimental evidence and expert analysis of POLE4’s function, localization, and involvement in DNA replication and genome maintenance. All claims are supported by the cited literature, reflecting the current understanding (as of 2023–2024) of the human POLE4 gene product.

Citations

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17. AnnotationURLCitation(end_index=5049, start_index=4911, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=we%20also%20observed%20a%20strong,Of%20note%2C%20while')
18. AnnotationURLCitation(end_index=5365, start_index=5215, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=stability%20of%20the%20whole%20Pol%CE%B5,Figures%20S1A%20and%20S1B')
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24. AnnotationURLCitation(end_index=7472, start_index=7350, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=DNA%20polymerase%20%CE%B5%20,In%20both')
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27. AnnotationURLCitation(end_index=8804, start_index=8628, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=observed%20in%20human%20patients%20harboring,normal%20development%20and%20tumor%20prevention')
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31. AnnotationURLCitation(end_index=10329, start_index=10179, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=Ohya%20et%C2%A0al,processivity%20on%20synthetic%20DNA%20substrates')
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35. AnnotationURLCitation(end_index=11569, start_index=11419, title='The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38828775/#:~:text=recombination%20deficiency,and%20hamper%20acquired%20PARPi%20resistance')
36. AnnotationURLCitation(end_index=11985, start_index=11829, title='Multiple roles of Pol epsilon in eukaryotic chromosome replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9022971/#:~:text=activation%2C%20while%20non,this%20minireview%2C%20we%20discuss%20recent')
37. AnnotationURLCitation(end_index=12328, start_index=12172, title='Multiple roles of Pol epsilon in eukaryotic chromosome replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9022971/#:~:text=activation%2C%20while%20non,this%20minireview%2C%20we%20discuss%20recent')
38. AnnotationURLCitation(end_index=12804, start_index=12648, title='Multiple roles of Pol epsilon in eukaryotic chromosome replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9022971/#:~:text=activation%2C%20while%20non,this%20minireview%2C%20we%20discuss%20recent')
39. AnnotationURLCitation(end_index=13296, start_index=13146, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=remodeling%20complexes%2C%20respectively%20%28Poot%20et%C2%A0al,39')
40. AnnotationURLCitation(end_index=13576, start_index=13400, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=observed%20in%20human%20patients%20harboring,normal%20development%20and%20tumor%20prevention')
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42. AnnotationURLCitation(end_index=14536, start_index=14378, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=During%20S%20phase%20of%20the,deposition%20of%20newly%20synthesized%20ones')
43. AnnotationURLCitation(end_index=14961, start_index=14829, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=Mammalian%20POLE3,H2B%20histone%20fold%20complex')
44. AnnotationURLCitation(end_index=15124, start_index=14962, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=Bellelli%20et%C2%A0al,dismantling%2Fmaturation%20at%20the%20replication%20fork')
45. AnnotationURLCitation(end_index=15479, start_index=15344, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=The%20POLE3,H4%20in%C2%A0vitro%20and%20in%C2%A0vivo')
46. AnnotationURLCitation(end_index=15642, start_index=15480, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=Bellelli%20et%C2%A0al,dismantling%2Fmaturation%20at%20the%20replication%20fork')
47. AnnotationURLCitation(end_index=15961, start_index=15829, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=Mammalian%20POLE3,H2B%20histone%20fold%20complex')
48. AnnotationURLCitation(end_index=16327, start_index=16157, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=POLE3%20contains%20a%20histone%20fold,superimposes%20with%20the%20recently%20published')
49. AnnotationURLCitation(end_index=16516, start_index=16328, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=structural%20model%20almost%20completely%20superimposes,POLE4%2C%20validating%20our%20structural%20model')
50. AnnotationURLCitation(end_index=17022, start_index=16840, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=Observations%20in%20budding%20and%20fission,maintenance%20of%20heterochromatin%20remains%20unclear')
51. AnnotationURLCitation(end_index=17380, start_index=17198, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=Observations%20in%20budding%20and%20fission,maintenance%20of%20heterochromatin%20remains%20unclear')
52. AnnotationURLCitation(end_index=17723, start_index=17541, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=Observations%20in%20budding%20and%20fission,maintenance%20of%20heterochromatin%20remains%20unclear')
53. AnnotationURLCitation(end_index=18293, start_index=18143, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=chaperone,dismantling%2Fmaturation%20at%20the%20replication%20fork')
54. AnnotationURLCitation(end_index=18768, start_index=18618, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=chaperone,dismantling%2Fmaturation%20at%20the%20replication%20fork')
55. AnnotationURLCitation(end_index=19438, start_index=19288, title='The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38828775/#:~:text=recombination%20deficiency,and%20hamper%20acquired%20PARPi%20resistance')
56. AnnotationURLCitation(end_index=19615, start_index=19439, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=observed%20in%20human%20patients%20harboring,normal%20development%20and%20tumor%20prevention')
57. AnnotationURLCitation(end_index=19957, start_index=19793, title='The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38828775/#:~:text=POLE3%20and%20POLE4%2C%20sensitizes%20cells,promising%20target%20to%20improve%20PARPi')
58. AnnotationURLCitation(end_index=20318, start_index=20154, title='The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38828775/#:~:text=POLE3%20and%20POLE4%2C%20sensitizes%20cells,promising%20target%20to%20improve%20PARPi')
59. AnnotationURLCitation(end_index=20696, start_index=20532, title='The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38828775/#:~:text=POLE3%20and%20POLE4%2C%20sensitizes%20cells,promising%20target%20to%20improve%20PARPi')
60. AnnotationURLCitation(end_index=21298, start_index=21148, title='The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38828775/#:~:text=recombination%20deficiency,and%20hamper%20acquired%20PARPi%20resistance')
61. AnnotationURLCitation(end_index=22241, start_index=22158, title='POLE4 | Abcam', type='url_citation', url='https://www.abcam.com/en-us/targets/pole4/20801#:~:text=Function')
62. AnnotationURLCitation(end_index=22408, start_index=22242, title='POLE4 DNA polymerase epsilon 4, accessory subunit [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene?Cmd=DetailsSearch&Db=gene&Term=56655#:~:text=POLE4%20is%20a%20histone,supplied%20by%20OMIM%2C%20Apr%202004')
63. AnnotationURLCitation(end_index=23122, start_index=22966, title='POLE4 protein expression summary - The Human Protein Atlas', type='url_citation', url='https://www.proteinatlas.org/ENSG00000115350-POLE4#:~:text=Subcellular%20location,i%7D%20Intracellular%20TISSUE%20RNA%20EXPRESSION')
64. AnnotationURLCitation(end_index=23507, start_index=23351, title='POLE4 protein expression summary - The Human Protein Atlas', type='url_citation', url='https://www.proteinatlas.org/ENSG00000115350-POLE4#:~:text=Subcellular%20location,i%7D%20Intracellular%20TISSUE%20RNA%20EXPRESSION')
65. AnnotationURLCitation(end_index=23913, start_index=23765, title='Protein structure - POLE4 - The Human Protein Atlas', type='url_citation', url='https://v23.proteinatlas.org/ENSG00000115350-POLE4/structure#:~:text=Structure%20prediction%20of%20Q9NR33%20from,predicted')
66. AnnotationURLCitation(end_index=24704, start_index=24591, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=match%20at%20L1811%20P,Google')
67. AnnotationURLCitation(end_index=24892, start_index=24779, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=match%20at%20L1811%20P,Google')
68. AnnotationURLCitation(end_index=25463, start_index=25294, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=Pol%CE%B5%20binding%20to%20double,studies%20using%20reconstituted%20human%20Pol%CE%B5')
69. AnnotationURLCitation(end_index=26294, start_index=26130, title='Multiple roles of Pol epsilon in eukaryotic chromosome replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9022971/#:~:text=Pol%20epsilon%20is%20a%20tetrameric,this%20minireview%2C%20we%20discuss%20recent')
70. AnnotationURLCitation(end_index=26555, start_index=26405, title='The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38828775/#:~:text=recombination%20deficiency,and%20hamper%20acquired%20PARPi%20resistance')
71. AnnotationURLCitation(end_index=27114, start_index=26938, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=observed%20in%20human%20patients%20harboring,normal%20development%20and%20tumor%20prevention')
72. AnnotationURLCitation(end_index=27544, start_index=27388, title='Multiple roles of Pol epsilon in eukaryotic chromosome replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9022971/#:~:text=activation%2C%20while%20non,this%20minireview%2C%20we%20discuss%20recent')
73. AnnotationURLCitation(end_index=27961, start_index=27805, title='Multiple roles of Pol epsilon in eukaryotic chromosome replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9022971/#:~:text=activation%2C%20while%20non,this%20minireview%2C%20we%20discuss%20recent')
74. AnnotationURLCitation(end_index=28371, start_index=28249, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=DNA%20polymerase%20%CE%B5%20,In%20both')
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76. AnnotationURLCitation(end_index=28850, start_index=28665, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=leading%20to%20embryonic%20lethality%20in,mice%20exhibit%20accelerated%20tumorigenesis%2C%20revealing')
77. AnnotationURLCitation(end_index=29180, start_index=28995, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=leading%20to%20embryonic%20lethality%20in,mice%20exhibit%20accelerated%20tumorigenesis%2C%20revealing')
78. AnnotationURLCitation(end_index=29627, start_index=29451, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=observed%20in%20human%20patients%20harboring,normal%20development%20and%20tumor%20prevention')
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80. AnnotationURLCitation(end_index=30330, start_index=30159, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=with%20replication%20stress%20and%20p53,normal%20development%20and%20tumor%20prevention')
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82. AnnotationURLCitation(end_index=31326, start_index=31143, title='The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38828775/#:~:text=their%20applicability%20beyond%20homologous%20recombination,sensitivity%20to%20PARPi%20and%20counteracts')
83. AnnotationURLCitation(end_index=31635, start_index=31471, title='The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38828775/#:~:text=POLE3%20and%20POLE4%2C%20sensitizes%20cells,promising%20target%20to%20improve%20PARPi')
84. AnnotationURLCitation(end_index=31898, start_index=31735, title='The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38828775/#:~:text=PARPi%20treatment%2C%20due%20to%20impaired,promising%20target%20to%20improve%20PARPi')
85. AnnotationURLCitation(end_index=32680, start_index=32558, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=DNA%20polymerase%20%CE%B5%20,In%20both')
86. AnnotationURLCitation(end_index=33090, start_index=32920, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=POLE3%20contains%20a%20histone%20fold,superimposes%20with%20the%20recently%20published')
87. AnnotationURLCitation(end_index=33358, start_index=33169, title='POLE4 DNA polymerase epsilon 4, accessory subunit [Homo sapiens (human)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene?Cmd=DetailsSearch&Db=gene&Term=56655#:~:text=Summary%20POLE4%20is%20a%20histone,enzymatic%20complexes%20for%20DNA%20transcription')
88. AnnotationURLCitation(end_index=33529, start_index=33394, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=The%20POLE3,H4%20in%C2%A0vitro%20and%20in%C2%A0vivo')
89. AnnotationURLCitation(end_index=33815, start_index=33665, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=Ohya%20et%C2%A0al,processivity%20on%20synthetic%20DNA%20substrates')
90. AnnotationURLCitation(end_index=33978, start_index=33816, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=Bellelli%20et%C2%A0al,dismantling%2Fmaturation%20at%20the%20replication%20fork')
91. AnnotationURLCitation(end_index=34435, start_index=34264, title='Multiple roles of Pol epsilon in eukaryotic chromosome replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9022971/#:~:text=Pol%20epsilon%20is%20a%20tetrameric,synthesis%2C%20DNA%20damage%20response%20signalling')
92. AnnotationURLCitation(end_index=34779, start_index=34597, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=Observations%20in%20budding%20and%20fission,maintenance%20of%20heterochromatin%20remains%20unclear')
93. AnnotationURLCitation(end_index=34941, start_index=34780, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=Here%20we%20show%20that%20the,important%20role%20in%20chromatin%20maintenance')
94. AnnotationURLCitation(end_index=35265, start_index=35083, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=Observations%20in%20budding%20and%20fission,maintenance%20of%20heterochromatin%20remains%20unclear')
95. AnnotationURLCitation(end_index=35575, start_index=35411, title='The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38828775/#:~:text=POLE3%20and%20POLE4%2C%20sensitizes%20cells,promising%20target%20to%20improve%20PARPi')
96. AnnotationURLCitation(end_index=35990, start_index=35834, title='POLE4 protein expression summary - The Human Protein Atlas', type='url_citation', url='https://www.proteinatlas.org/ENSG00000115350-POLE4#:~:text=Subcellular%20location,i%7D%20Intracellular%20TISSUE%20RNA%20EXPRESSION')
97. AnnotationURLCitation(end_index=36333, start_index=36235, title='POLE4 | Abcam', type='url_citation', url='https://www.abcam.com/en-us/targets/pole4/20801#:~:text=Cellular%20localization')
98. AnnotationURLCitation(end_index=36713, start_index=36550, title='Multiple roles of Pol epsilon in eukaryotic chromosome replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9022971/#:~:text=function%20is%20dispensable%20for%20viability,the%20multiple%20roles%20of%20Pol')
99. AnnotationURLCitation(end_index=36982, start_index=36826, title='Multiple roles of Pol epsilon in eukaryotic chromosome replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9022971/#:~:text=activation%2C%20while%20non,this%20minireview%2C%20we%20discuss%20recent')
100. AnnotationURLCitation(end_index=37310, start_index=37134, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=observed%20in%20human%20patients%20harboring,normal%20development%20and%20tumor%20prevention')
101. AnnotationURLCitation(end_index=37601, start_index=37425, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=observed%20in%20human%20patients%20harboring,normal%20development%20and%20tumor%20prevention')
102. AnnotationURLCitation(end_index=37990, start_index=37828, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=Bellelli%20et%C2%A0al,dismantling%2Fmaturation%20at%20the%20replication%20fork')
103. AnnotationURLCitation(end_index=38249, start_index=38127, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=DNA%20polymerase%20%CE%B5%20,In%20both')
104. AnnotationURLCitation(end_index=38426, start_index=38250, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=observed%20in%20human%20patients%20harboring,normal%20development%20and%20tumor%20prevention')
105. AnnotationURLCitation(end_index=38815, start_index=38651, title='The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38828775/#:~:text=POLE3%20and%20POLE4%2C%20sensitizes%20cells,promising%20target%20to%20improve%20PARPi')
106. AnnotationURLCitation(end_index=39270, start_index=39107, title='Multiple roles of Pol epsilon in eukaryotic chromosome replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9022971/#:~:text=function%20is%20dispensable%20for%20viability,the%20multiple%20roles%20of%20Pol')
107. AnnotationURLCitation(end_index=39830, start_index=39668, title='POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC6179962/#:~:text=Bellelli%20et%C2%A0al,dismantling%2Fmaturation%20at%20the%20replication%20fork')
108. AnnotationURLCitation(end_index=39976, start_index=39854, title='Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC5972231/#:~:text=DNA%20polymerase%20%CE%B5%20,In%20both')
109. AnnotationURLCitation(end_index=40184, start_index=40020, title='Multiple roles of Pol epsilon in eukaryotic chromosome replication - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9022971/#:~:text=Pol%20epsilon%20is%20a%20tetrameric,this%20minireview%2C%20we%20discuss%20recent')
110. AnnotationURLCitation(end_index=40386, start_index=40222, title='The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/38828775/#:~:text=POLE3%20and%20POLE4%2C%20sensitizes%20cells,promising%20target%20to%20improve%20PARPi')