POLD1 - Knowledge (XXG)

1634: 1796:(DSB) repair. POLD1 mediates the post-incision steps in BER, NER and MMR. Polδ interacts with the MMR machinery to support post-replication proofreading of newly synthesized DNA, with cells bearing mutations that inactivate POLD1 and MMR components experiencing elevated mutation rates. As noted above, a Polδ heterotrimer (Polδ3) becomes the dominant oligomeric form of POLD1 and is active during the presence of DNA damage. Polδ3 is less error-prone than (Polδ4), and can discriminate better between mismatched pairs, associated with better proofreading activity: however, it has reduced ability to bypass some base lesions. Instead, Polδ polymerase switching to the specialized 1644:(extracted on 03/31/2016). POLD1 is centered (light green box) with red lines indicating its interactions. The light blue boxes represent interactions of the core complex. The light pink boxes represent other putative interactions in DNA repair and replication. Grey lines represent established and putative interactions between the other represented proteins. The network was mapped by using Cytoscape. The interactions represent high- confidence experimental data extracted from BIND, DIP, GRID, HPRD, IntAct, MINT, and PID curated by STRING. The experimental scores are derived from assays on affinity binding and chromatography. 244: 221: 1800:(Polζ) is important for TLS as the substitution of p125 for the Polζ catalytic subunit, p353, permits better bypass activity. In this process, the highly conserved C-terminal domain (CTD) of POLD1/p125 interacts with the CTD domain of Polζ, and the iron clusters within each CTD mediate interactions involving binding to POLD2 that permit polymerase switching during TLS. Some recent studies suggest that a switch from Polδ to Pol lambda (λ) also supports the TLS and repair of oxidative DNA damage like 118: 143: 1474:-rich metal-binding motifs (CysA and CysB) (from 1012 and 1083) required for proliferating cell nuclear antigen (PCNA) binding and recruitment of accessory subunits respectively. CysB coordinates an cluster added through Cytosolic Iron-sulfur protein Assembly (CIA), which requires the function of the mitochondrial Iron Sulfur Cluster (ISC) assembly machinery. The maturation process is mediated by the core targeting complex CIA1-CIA2B/FAM96B- 495: 1404:(go-ichi-ni-san) which has four subunits: Sld5, Psf1, Psf2 and Psf3. GINS interact with Polε to initiate DNA synthesis. Recent evidence also suggests a role for Polδ in leading strand synthesis. PCNA stimulates both polymerases (proliferating cell nuclear antigen; red ring). The RFC (replication factor C) complex with RPA acts as a clamp loader for PCNA onto the DNA. The lagging strand is synthesized in short fragments called the 250: 149: 1482: 1387: 2138: 1755:

produce when defective. Maintenance of replication fidelity is a fine balance between the unique errors by polymerases δ and ε, the equilibrium between proofreading and MMR, and distinction in ribonucleotide processing between the two strands. Extensive studies in yeast models have shown that mutations in the exonuclease domain of Polδ and Polε homologues can cause a

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the calf thymus, and the complete holoenzyme was very strongly stimulated by PCNA. Numerous studies have shown that while POLD1 possesses both the polymerase and the 3’-5’ exonuclease proofreading activity, the other subunits increase these activities, DNA binding abilities, and functionally important interactions with PCNA and its clamp loader

1255:(kDa). The polymerase catalytic subunit was identified as the 125 kDa polypeptide by activity staining in 1991. Several groups independently cloned the human and murine POLD1 cDNAs. Following its purification from various sources including calf thymus, human placenta, and HeLa cells, its activity was implicated in DNA repair. 1827:, HR mechanisms could restart stalled replication forks by utilizing Polδ strand synthesis activity, but such nonallelic HR-mediated restart is very error prone potentially leading to increased genomic instability. Polδ structurally and functionally interacts with the WRN protein, and WRN recruits Polδ to the nucleolus. The 1489:

ligands for the metal ions required for catalysis are shown in bold (D316 and E318 in the ExoI motif, D402 in the ExoII motif and D515 in the ExoIII motif). Y511 (underlined) defines p125 of the DDEDy-type of exonuclease superfamilies according to the Zuo and Deutscher nomenclature, and is required for catalysis.

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variant, c.1812_1814delCTC p.Ser605del (rs398122386). S605 is in the highly conserved motif A of the polymerase active site. This variant does not inhibit the DNA binding activity but impacts catalysis. Another variant has been reported in a separate patient (p.R507C). This variant is located in the

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A number of other studies and screens have identified additional interaction partners relevant to functions in DNA replication and repair. Figure 3 shows a matrix of established and putative interactions during replication and repair which can be further accessed through and. A website at Vanderbilt

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is ~34 kb long and its cytogenetic location is chromosome 19 q13.33. The precise location, in the GRCh38.p2 assembly, is from base pair 50,384,290 to base pair 50,418,018 on chromosome 19. The mouse orthologue maps to mouse chromosome 7. In humans, the major POLD1 transcript (NM_002691.3) contains 27

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Binding and association studies have shown that POLD2 is tightly associated with POLD1; POLD3 and POLD2 interact with each other and POLD4 interacts with both POLD1 and POLD2. Polδ heterotetramer reconstituted by coexpression of subunits in Sf9 cells had properties were similar to Polδ purified from

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coding exons (26) and at least 20 bases into the adjacent non-coding regions. For families with known mutations, single site testing is also available to confirm the presence of a mutation. The availability of these genetic tests has opened up new possibilities for cancers previously classified as

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have also been observed in patients with a syndrome known as mandibular hypoplasia, deafness, and progeroid features with lipodystrophy (MDPL/MDP) syndrome (#615381 in the Online Mendelian Inheritance in Man (OMIM) database). This is a very rare syndrome, and few studies describing mutations have

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Motifs I to III are conserved in the B-family of polymerases. Motifs IV and V were recently described as conserved between Polδ and Polε. This domain also has 3 sequence motifs (ExoI, ExoII and ExoIII) that have a specific YX(3)D pattern at ExoIII. The 4 conserved acid residues DEDD that serve as

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has been observed. although no clinical significance has been associated with this phenotype as yet. Studies are also underway to understand if there is a relation between these pathologies or these mutations and a predisposition to cancer. Currently proposed mechanisms by which POLD1 defects are

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and 3'-exonuclease (or the proofreading) activity. Recent studies have contended that Polδ may synthesize the leading strand. How these polymerases function, in relationship with other factors involved in replication, is of great interest as it likely explains the mutational landscape that they

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disorder) leading to accelerated aging and increased genetic instability. The interaction with WRN increases the processivity of Polδ in a PCNA-independent manner. Through these interactions WRN directly impacts DNA replication-repair and assists in Polδ-mediated synthesis.

1691:), the POLD4/p12 subunit is rapidly degraded. The catalytic activities of p125 are different whether it is in the heterotetramer (Polδ4, with p12) or in the heterotrimer (Polδ3, without p12). The production of the heterotrimer depends on p12 degradation by the 1950:

and biallelic mismatch repair deficiency (bMMRD), leads to ultra-hypermutated tumor phenotypes. Such phenotypes as ultra-hypermutation in tumors may indicate better response to newer cancer therapeutics in development, although this needs direct evaluation for

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University provides additional interaction on important POLD1 protein structure and various classes of gene and protein interaction, based on criteria such as co-occurrence in a complex, direct physical interaction, regulatory relationship, and co-expression.

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POLD1 Ser605del and R507C variants have also been identified in a subset of patients with atypical Werner’s syndrome (AWS). After molecular testing, these patients were reclassified as MDPL/MDP patients. MDPL/MDP, AWS and Werner’s syndrome all present with

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Pelosini C, Martinelli S, Ceccarini G, et al. (November 2014). "Identification of a novel mutation in the polymerase delta 1 (POLD1) gene in a lipodystrophic patient affected by mandibular hypoplasia, deafness, progeroid features (MDPL) syndrome".

2029:, and short stature (also knowns as the FILS syndrome). The second one presented with more severe symptoms. These cases join a growing number of developmental defects associated with inherited mutations targeting the function of polymerase genes. 8894: 1763:

mutations. DNA-binding proteins that rapidly reassociate post-replication prevent Polδ from repairing errors produced by Polα in the mature lagging strand. Yeast studies have shown that Polδ can proofread Polε errors on the leading strand.

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mutations which include: 1) Occurrence of 20-100 adenomas, and 2) Family history that meets the Amsterdam II criteria for colorectal and endometrial cancers. Current clinical testing guidelines for families with mutations in

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Dresler SL, Kimbro KS (May 1987). "2',3'-Dideoxythymidine 5'-triphosphate inhibition of DNA replication and ultraviolet-induced DNA repair synthesis in human cells: evidence for involvement of DNA polymerase delta".

2110:. Another recent study showed that mutations affecting Polδ and Polε mutations can co-occur along with MMR mutations. This suggests panel gene testing should include MMR and Pol genes even in patients with MSI. 1867:

DNA repair proteins have been shown to be important in human diseases including cancer. For example, germline mutations in DNA repair proteins involved in MMR (MSH2, MLH1, MSH6, and PMS2) have been described in

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pathogenic focus on the idea of replication defects leading to genomic instability and checkpoint activation, ultimately leading to cell death or cellular senescence. Alternatively, Polδ is associated with

2011:. A first example of germline transmission was observed in a mother and son with the Ser605del mutation. Recently, two independent studies identified patients with the same homozygous splice variant in 1424:

end (residues 4-19). Residues 304-533 contain the exonuclease domain (Figure 2) while residues 579-974 contain the polymerase domain. The exonuclease domain is a DEDDy-type DnaQ-like domain common to the

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and his colleagues in 1956, reviewed in. In 1976, Byrnes et al. discovered a third DNA polymerase activity in mammalian cells that was called polymerase delta (δ). It was purified from rabbit erythroid

1400:(RPA) (light pink). Polα bound to a primase, initiates lagging strand synthesis (blue line), herein an RNA primer is first elongated by Polα and then by Polδ. Leading strand (black line) shows Polε and 7782:

Reinier F, Zoledziewska M, Hanna D, et al. (November 2015). "Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome in the context of inherited lipodystrophies".

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Popanda O, Flohr T, Fox G, et al. (November 1999). "A mutation detected in DNA polymerase delta cDNA from Novikoff hepatoma cells correlates with abnormal catalytic properties of the enzyme".

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The POLD1/P125 protein is expressed ubiquitously across a panel of human tissues with high levels in the heart and lung tissues. The subcellular localization of POLD1/p125 is predominantly in the

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Bouffet E, Larouche V, Campbell BB, et al. (March 2016). "Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency".

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variants have been clinically identified which have been predicted to be damaging and are currently under further investigation (e.g., p. D316H, p. D316G, p. R409W, p. L474P and p. P327L).

1750:(Polε). After initiation of DNA synthesis by Polα, Polδ or Polε execute lagging and leading strand synthesis, respectively. These polymerases maintain a very high fidelity, which is ensured by 7205:

Shlien A, Campbell BB, de Borja R, et al. (March 2015). "Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers".

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exons and translates into the 1107 amino acids of the p125 or A subunit. A longer isoform has been reported with a 26 amino acid in-frame insertion after amino acid 592 (NP_001295561.1). A

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Lee SY, Lee H, Kim ES, et al. (April 2015). "WRN translocation from nucleolus to nucleoplasm is regulated by SIRT1 and required for DNA repair and the development of chemoresistance".

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of cell cycle. The polymerase domain also has a highly conserved KKRY motif (residues 806 to 809) which is important for the binding and catalytic function. POLD1 can be targeted to the

1440:, in motif A (DXXLYPS, D602) and motif C (DTDS, D757) that bind calcium at the active site. Motif A has 11 amino acids that are important in nucleotide incorporation and formation of the 1358:

transcription by indirect p21-dependent activation of a p53-p21-DREAM-CDE/CHR pathway. One study has reported that the p53 tumor suppressor protein competes with Sp1 for binding to the

1284:(LOC100422453) has been reported on the long arm of chromosome 6. Table 1 provides gene names and chromosomal locations for the various subunits of Polδ in humans, mice, budding yeast ( 7285:"Association of Polymerase e-Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1" 1154:

domains, which provide the protein an important second function in proofreading to ensure replication accuracy during DNA synthesis, and in a number of types of replication-linked

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POLD1/p125 has a NoDS domain that regulates transport to the nucleolus in response to acidosis. Nucleolar transport requires a direct interaction between the p50 subunit and the

1412:(ligase I). Replication errors that are not corrected by the polymerases (light grey box on the new leading strand) are further repaired by post-replication mismatch repair (MMR). 1811:

can halt cell cycle at G1 and G2/M phases in human cells. Cell cycle block in these phases typically indicates presence of DNA damage and activation of DNA damage checkpoints.

4820:"Protein arginine methyltransferase 7 regulates cellular response to DNA damage by methylating promoter histones H2A and H4 of the polymerase δ catalytic subunit gene, POLD1" 1633: 6780:"POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance" 3872:"Structural and biochemical investigation of the role in proofreading of a beta hairpin loop found in the exonuclease domain of a replicative DNA polymerase of the B family" 2831:

Lee MY, Tan CK, So AG, et al. (May 1980). "Purification of deoxyribonucleic acid polymerase delta from calf thymus: partial characterization of physical properties".

7191: 5029:"The tail that wags the dog: p12, the smallest subunit of DNA polymerase δ, is degraded by ubiquitin ligases in response to DNA damage and during cell cycle progression" 257: 156: 1220:

bone marrow and described as a DNA polymerase that possessed an intrinsic 3’ to 5’ exonuclease activity. A 3’-5’ exonuclease proofreading function for DNA polymerases (

1759:, reviewed in. The single stranded (ss) DNA synthesized during lagging strand synthesis can be targeted by ss-DNA damaging agents as well as is a selective target for 1164:

impairing activity of POLD1 have been implicated in several types of hereditary cancer, in some sporadic cancers, and in a developmental syndrome of premature aging,

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Lee MY, Toomey NL (February 1987). "Human placental DNA polymerase delta: identification of a 170-kilodalton polypeptide by activity staining and immunoblotting".

4947:"Reconstitution of human DNA polymerase delta using recombinant baculoviruses: the p12 subunit potentiates DNA polymerizing activity of the four-subunit enzyme" 4723:"Decreased gene expression responsible for post-ultraviolet DNA repair synthesis in aging: a possible mechanism of age-related reduction in DNA repair capacity" 1721:

protein. During DNA damage response, WRN moves out of the nucleolus and thereby releases Polδ. POLD1/p125 has also been shown to interact with PDIP46/SKAR and

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Boyer AS, Walter D, Sørensen CS (January 2016). "DNA replication and cancer: From dysfunctional replication origin activities to therapeutic opportunities".

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Cullmann G, Hindges R, Berchtold MW, et al. (December 1993). "Cloning of a mouse cDNA encoding DNA polymerase delta: refinement of the homology boxes".

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DNA replication is a highly organized process that involves many enzymes and proteins, including several DNA polymerases. The major replicative activity in

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upon acidification via a nucleolar detention sequence (NoDS) motif represented by small sequence motifs dispersed throughout the protein coding region. The

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and endometrial cancer screening (beginning at 40 for female carriers). Currently studies are underway to determine the exact cancer risk from specific

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Xie B, Mazloum N, Liu L, et al. (November 2002). "Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme".

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Lee MY, Tan CK, Downey KM, et al. (April 1984). "Further studies on calf thymus DNA polymerase delta purified to homogeneity by a new procedure".

1334:. Another regulatory element, the cell cycle element/cell cycle genes homology region (CDE/CHR), located downstream of the start site is important for 834: 79: 8147: 1869: 2648:"Enzymatic synthesis of deoxyribonucleic acid. XXXVI. A proofreading function for the 3 5′ exonuclease activity in deoxyribonucleic acid polymerase" 2604:

Byrnes JJ, Downey KM, Black VL, et al. (June 1976). "A new mammalian DNA polymerase with 3' to 5' exonuclease activity: DNA polymerase delta".

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Zhang Q, Zhang Q, Chen H, et al. (February 2016). "Multiple forms of human DNA polymerase delta sub-assembling in cellular DNA transactions".

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Crute JJ, Wahl AF, Bambara RA (January 1986). "Purification and characterization of two new high molecular weight forms of DNA polymerase delta".

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been reported. The mutations that have been observed are in the regions that affect the exonuclease domain and polymerase domains. Five unrelated

1801: 3557:"miR-155 Overexpression Promotes Genomic Instability by Reducing High-fidelity Polymerase Delta Expression and Activating Error-Prone DSB Repair" 6208:"DNA damage alters DNA polymerase delta to a form that exhibits increased discrimination against modified template bases and mismatched primers" 4359:"The 3' to 5' exonuclease activity located in the DNA polymerase delta subunit of Saccharomyces cerevisiae is required for accurate replication" 8711: 8674: 1816: 1718: 2122:

genetically undefined colorectal cancers or colorectal cancer type “X”. Resources for clinical testing for MDPL/MDP have also been developed.

1498:(RFC). The DNA Polδ holoenzyme is often considered to include PCNA and RFC as well as the four subunits of the polymerase complex (Figure 1). 8889: 2299: 2281: 7043:"Genetic Variants That Predispose to DNA Double-Strand Breaks in Lymphocytes From a Subset of Patients With Familial Colorectal Carcinomas" 5078:"A novel function of CRL4(Cdt2): regulation of the subunit structure of DNA polymerase δ in response to DNA damage and during the S phase" 7577: 7560: 6994:"Exonuclease mutations in DNA polymerase epsilon reveal replication strand specific mutation patterns and human origins of replication" 3606:"Genome-wide binding studies reveal DNA binding specificity mechanisms and functional interplay amongst Forkhead transcription factors" 243: 8794: 1667:

regulated in response to DNA damage. Other studies have also shown that POLD1/p125 expression is regulated by miR-155, p53 and by the

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Table 1: Gene names and chromosomal locations for the various subunits of polymerase delta in human, mouse, budding and fission yeast.

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Song N, Zhu X, Shi L, et al. (June 2009). "Identification and functional analysis of a CDE/CHR element in the POLD1 promoter".

1076: 7917:"Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome")" 220: 7694:"Mutation at the polymerase active site of mouse DNA polymerase delta increases genomic instability and accelerates tumorigenesis" 4775:

Wang JL, Guo HL, Wang PC, et al. (December 2012). "Age-dependent down-regulation of DNA polymerase δ1 in human lymphocytes".

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CRL4 can degrade POLD4/p12 during normal DNA replication and in the presence of DNA damage. POLD4/p12 can also be degraded by the

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Wahl AF, Crute JJ, Sabatino RD, et al. (December 1986). "Properties of two forms of DNA polymerase delta from calf thymus".

1847: 2268: 2247: 1964: 3372:"The human POLD1 gene. Identification of an upstream activator sequence, activation by Sp1 and Sp3, and cell cycle regulation" 1433:

structure that helps in switching between the polymerase and exonuclease active sites in case of nucleotide misincorporation.

8716: 142: 117: 6516:"The Werner syndrome exonuclease facilitates DNA degradation and high fidelity DNA polymerization by human DNA polymerase δ" 2264: 5129:"Proteolysis of the human DNA polymerase delta smallest subunit p12 by μ-calpain in calcium-triggered apoptotic HeLa cells" 3328:"Transcriptional regulation of the human DNA polymerase delta catalytic subunit gene POLD1 by p53 tumor suppressor and Sp1" 2708:"Characterization of human DNA polymerase delta and its immunochemical relationships with DNA polymerase alpha and epsilon" 8526: 8376: 8140: 7561:"Detection of mutations in the DNA polymerase delta gene of human sporadic colorectal cancers and colon cancer cell lines" 6676:"Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas" 6836:"Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers" 2243: 7966:"A patient with polymerase E1 deficiency (POLE1): clinical features and overlap with DNA breakage/instability syndromes" 1416:

POLD1/p125 has a common B-family fold, similar to other DNA polymerases (Polα and ε). Human POLD1/p125 has a putative

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as the sugar steric gate that prevents ribonucleotide incorporation. An LXCXE motif (711 to 715) mediates binding to

1417: 4408:"Evolution of replicative DNA polymerases in archaea and their contributions to the eukaryotic replication machinery" 2145:

The 2016 version of this article was updated by an external expert under a dual publication model. The corresponding

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da Costa LT, Liu B, el-Deiry W, et al. (January 1995). "Polymerase delta variants in RER colorectal tumours".

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are the name and gene symbol approved by the Human Genome Organization (HUGO) Gene Nomenclature Committee (HGNC).

1396:. The Polδ complex (p125, p66, p50 and p12) associates with replication fork. Single-stranded DNA are coated with 249: 148: 50:, CDC2, CRCS10, MDPL, POLD, polymerase (DNA) delta 1, catalytic subunit, DNA polymerase delta 1, catalytic subunit 8700: 6418:"A synthetic lethal screen identifies ATR-inhibition as a novel therapeutic approach for POLD1-deficient cancers" 1292: 6159:"Sensitivity to phosphonoacetic acid: a new phenotype to probe DNA polymerase delta in Saccharomyces cerevisiae" 3237:

Goldsby RE, Singh M, Preston BD (January 1998). "Mouse DNA polymerase delta gene (Pold1) maps to chromosome 7".

8861: 8133: 3112:"Primary structure of the catalytic subunit of human DNA polymerase delta and chromosomal location of the gene" 2347:"Primary structure of the catalytic subunit of human DNA polymerase delta and chromosomal location of the gene" 1851: 1699: 1331: 1319: 1315: 1286: 898: 67: 4650:"An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy" 2526:

Kornberg A, Kornberg SR, Simms ES (April 1956). "Metaphosphate synthesis by an enzyme from Escherichia coli".

1886:, the catalytic subunit of Polε. These mutations are associated with oligo-adenomatous polyposis, early-onset 8081: 8263: 8194: 1956: 1680: 879: 3831:"Interaction of the retinoblastoma protein (pRb) with the catalytic subunit of DNA polymerase delta (p125)" 8760: 8691: 1455: 1397: 1226:) had first been described 4 years earlier by Kornberg and Brutlag, reviewed in. The human DNA Polδ is a 2480: 8686: 8455: 8125: 7185: 2164:"POLD1: Central mediator of DNA replication and repair, and implication in cancer and other pathologies" 2146: 1781: 131: 8015:

Guénantin AC, Briand N, Bidault G, et al. (May 2014). "Nuclear envelope-related lipodystrophies".

8733: 8706: 8657: 6616:"Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers" 6319: 5964: 5461: 5370:"PDIP46 (DNA polymerase δ interacting protein 46) is an activating factor for human DNA polymerase δ" 5237: 5140: 4215: 4158: 3123: 2428: 2358: 1785: 1495: 1196: 1139: 2671:

Reha-Krantz LJ (May 2010). "DNA polymerase proofreading: Multiple roles maintain genome stability".

1963:(P436H in one, S461P in the other), and showed a durable response to a clinical trial with the anti- 1310:

reaches a peak in late G1/S phase during DNA replication. The POLD1 promoter is G/C-rich and has no

46: 8463: 5904:"APOBEC3A and APOBEC3B Preferentially Deaminate the Lagging Strand Template during DNA Replication" 1933:

mutation p. S478N, in the exonuclease domain, has been validated as damaging and pathogenic. Other

1854:-related mechanism involving template switching that employs polymerase δ-dependent DNA synthesis. 1777: 1668: 1441: 1172: 1027: 1023: 972: 968: 3756: 2057:

The hereditary colorectal cancers (CRCs) associated with mutations in the proofreading ability of

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Polδ mutation in mice that disrupts enzymatic function leads to highly elevated cancer incidence.

7674: 7541: 7498: 7230: 7119: 6732:"New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis" 5315: 4800: 4697: 4493: 4184: 4057:"Eukaryotic DNA polymerases require an iron-sulfur cluster for the formation of active complexes" 3485: 3413:"The CHR site: definition and genome-wide identification of a cell cycle transcriptional element" 3262: 2629: 2586: 2508: 2078: 2018: 1891: 1773: 91: 7284: 3214:"POLD1 polymerase (DNA) delta 1, catalytic subunit [Homo sapiens (human)] - Gene - NCBI" 2098:(every 1–2 years), gastroduodenoscopies (every 3 years) starting early (20-25), possibility for 1052: 1031: 997: 976: 4261:"A novel POLE mutation associated with cancers of colon, pancreas, ovaries and small intestine" 1663:

human skin fibroblasts and in lymphocytes from an elderly population. POLD1/p125 expression is

8669: 8486: 8105: 8032: 7997: 7946: 7897: 7848: 7799: 7764: 7723: 7666: 7631: 7582: 7533: 7490: 7448: 7399: 7358: 7309: 7265: 7222: 7173: 7111: 7072: 7023: 6971: 6919: 6865: 6809: 6753: 6705: 6645: 6596: 6547: 6496: 6447: 6398: 6347: 6288: 6237: 6188: 6139: 6090: 6041: 5990: 5933: 5884: 5835: 5786: 5737: 5688: 5639: 5590: 5538: 5489: 5430: 5399: 5350: 5307: 5265: 5203: 5168: 5109: 5058: 5009: 4968: 4927: 4886: 4851: 4792: 4754: 4679: 4474: 4439: 4388: 4339: 4290: 4241: 4176: 4127: 4086: 4037: 3993: 3944: 3893: 3852: 3811: 3738: 3687: 3635: 3586: 3534: 3477: 3442: 3393: 3349: 3303: 3254: 3192: 3151: 3065: 3024: 2988: 2953: 2918: 2883: 2848: 2813: 2778: 2729: 2688: 2621: 2578: 2543: 2500: 2454: 2386: 2203: 2185: 1930: 1887: 1756: 1436:

Motifs A and C, which are the most conserved of the polymerase domain. These have 2 catalytic

1405: 1161: 39: 5561:"A Major Role of DNA Polymerase δ in Replication of Both the Leading and Lagging DNA Strands" 4106:"Biogenesis of cytosolic and nuclear iron-sulfur proteins and their role in genome stability" 8626: 8475: 8470: 8362: 8024: 7987: 7977: 7936: 7928: 7887: 7879: 7838: 7830: 7791: 7756: 7713: 7705: 7658: 7621: 7613: 7572: 7525: 7482: 7438: 7430: 7389: 7348: 7340: 7299: 7257: 7214: 7163: 7153: 7103: 7062: 7054: 7013: 7005: 6961: 6953: 6909: 6901: 6855: 6847: 6799: 6791: 6743: 6695: 6687: 6635: 6627: 6586: 6578: 6537: 6527: 6486: 6478: 6467:"Polymerase δ replicates both strands after homologous recombination-dependent fork restart" 6437: 6429: 6388: 6378: 6337: 6327: 6278: 6268: 6227: 6219: 6178: 6170: 6129: 6121: 6080: 6072: 6031: 6021: 5980: 5972: 5923: 5915: 5874: 5866: 5825: 5817: 5776: 5768: 5727: 5719: 5678: 5670: 5629: 5621: 5580: 5572: 5528: 5520: 5479: 5469: 5422: 5389: 5381: 5342: 5299: 5255: 5245: 5195: 5158: 5148: 5099: 5089: 5048: 5040: 4999: 4958: 4917: 4878: 4841: 4831: 4784: 4744: 4734: 4669: 4661: 4466: 4429: 4419: 4378: 4370: 4329: 4321: 4280: 4272: 4231: 4223: 4166: 4117: 4076: 4068: 4027: 3983: 3975: 3934: 3924: 3883: 3842: 3801: 3793: 3728: 3718: 3677: 3669: 3625: 3617: 3576: 3568: 3524: 3516: 3469: 3432: 3424: 3383: 3339: 3293: 3246: 3182: 3141: 3131: 3055: 3016: 2980: 2945: 2910: 2875: 2840: 2805: 2768: 2760: 2719: 2680: 2613: 2570: 2535: 2492: 2444: 2436: 2376: 2366: 2211: 2193: 2177: 2066: 2042: 2022: 1994: 1703: 1684: 1252: 1222: 1208: 1192: 336: 267: 211: 166: 4988:"A novel DNA damage response: rapid degradation of the p12 subunit of dna polymerase delta" 494: 87: 8839: 8631: 8505: 8223: 8173: 8156: 7819:"Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions" 4619: 4517: 4016:"Immobilization of proteins in the nucleolus by ribosomal intergenic spacer noncoding RNA" 2082: 1876:(MSI). More recently, germline mutations have been reported in the exonuclease domains of 1832: 1212: 1143: 311: 4869:

Cui M, You L, Ren X, et al. (February 2016). "Long non-coding RNA PVT1 and cancer".

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mutations linked to cancer are present in the exonuclease domain. In contrast to LS, the

6323: 6308:"A switch between DNA polymerases δ and λ promotes error-free bypass of 8-oxo-G lesions" 5968: 5465: 5241: 5144: 4219: 4204:"MMS19 assembles iron-sulfur proteins required for DNA metabolism and genomic integrity" 4162: 3127: 2432: 2362: 1183:). Studies of POLD1 emphasize the importance of maintaining genomic stability to limit 8479: 8459: 7992: 7965: 7941: 7916: 7892: 7867: 7843: 7818: 7718: 7693: 7626: 7601: 7443: 7418: 7353: 7329:"POLE Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer" 7328: 7168: 7141: 7067: 7042: 7018: 6993: 6966: 6941: 6914: 6889: 6860: 6835: 6804: 6779: 6700: 6675: 6640: 6615: 6591: 6566: 6542: 6515: 6491: 6466: 6442: 6417: 6393: 6366: 6342: 6307: 6283: 6256: 6232: 6207: 6183: 6158: 6125: 6085: 6060: 6036: 6009: 5985: 5952: 5928: 5903: 5879: 5854: 5830: 5805: 5781: 5756: 5732: 5707: 5683: 5658: 5634: 5609: 5585: 5560: 5533: 5508: 5484: 5449: 5394: 5369: 5163: 5128: 5104: 5077: 5053: 5028: 4846: 4819: 4674: 4649: 4434: 4407: 4374: 4285: 4260: 4236: 4203: 4081: 4056: 3988: 3963: 3939: 3912: 3806: 3781: 3733: 3706: 3682: 3657: 3630: 3605: 3581: 3556: 3529: 3504: 3437: 3412: 3171:"Human DNA polymerase delta gene maps to region 19q13.3-q13.4 by in situ hybridization" 2749:"Molecular cloning of the cDNA for the catalytic subunit of human DNA polymerase delta" 2449: 2416: 2198: 2168: 2163: 1797: 1747: 1743: 1426: 1227: 1184: 1147: 6134: 6109: 5199: 4542:"Cancer Cell Metabolism Database ~~ Bioinformatics and Systems Medicine Laboratory ~~" 4383: 4358: 3187: 3170: 3060: 3043: 2773: 2748: 2724: 2707: 1481: 768: 763: 758: 753: 748: 743: 738: 733: 728: 723: 718: 713: 708: 703: 698: 693: 688: 683: 678: 662: 657: 652: 647: 642: 637: 632: 616: 611: 606: 601: 596: 591: 586: 581: 576: 571: 566: 561: 556: 551: 546: 541: 536: 8883: 8681: 8608: 8218: 8114: 5260: 5225: 4739: 4722: 4334: 4309: 3146: 3111: 2809: 2539: 2381: 2346: 2159: 1895: 1882: 1448: 1437: 1303: 1176: 523: 7678: 7617: 7545: 7502: 7123: 5426: 4804: 4188: 3489: 3266: 2647: 2633: 2590: 2561:

Friedberg EC (February 2006). "The eureka enzyme: the discovery of DNA polymerase".

8820: 7234: 5319: 4596:"Cytoscape: An Open Source Platform for Complex Network Analysis and Visualization" 2512: 1649: 1430: 1180: 329: 108: 7795: 7760: 7394: 7377: 7344: 4310:"Exoribonuclease superfamilies: structural analysis and phylogenetic distribution" 3673: 3572: 1386: 71: 8028: 7058: 6257:"DNA polymerase δ and ζ switch by sharing accessory subunits of DNA polymerase δ" 6026: 5919: 5772: 5723: 5674: 5576: 5524: 5346: 5153: 4122: 4105: 4032: 4015: 3298: 3281: 2684: 2317: 2003:

highly conserved ExoIII domain and has not been completely characterized as yet.

1478:, which interacts with the apoprotein to ensure specific Fe-S cluster insertion. 95: 8765: 7304: 6174: 6076: 2304:

National Center for Biotechnology Information, U.S. National Library of Medicine

2286:

National Center for Biotechnology Information, U.S. National Library of Medicine

2099: 2095: 2046: 2013: 1946: 1899: 1688: 1676: 1664: 1653: 1217: 1151: 7868:"POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome" 6312: