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POLD1

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Template:PBB DNA polymerase delta catalytic subunit is an enzyme that in humans is encoded by the POLD1 gene.[1][2] It is a component of the DNA polymerase delta complex.

POLD1 along with POLE (enzyme) is associated with multiple adenoma.[3]

The gene polymerase delta 1 (POLD1) encodes the large, POLD1/p125, catalytic subunit of the DNA polymerase delta (Polδ) complex.[4][5] The Polδ enzyme is responsible for synthesizing the lagging strand of DNA, and has also been implicated in some activities at the leading strand. The POLD1/p125 subunit encodes both DNA polymerizing and DNA repair 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 DNA repair following DNA damage. Germline mutations 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, Mandibular hypoplasia, Deafness, and Progeroid features and Lipodystrophy (MDPL/MDP syndrome). Studies of POLD1 emphasize the importance of maintaining genomic stability to limit tumorigenesis. It is currently unclear whether the enhanced tumorigenesis associated with germline POLD1 defects is the result of increased base substitutions or due to fork collapse and production of DNA double strand breaks (DSBs).[5][6]

Discovery

The first DNA polymerase, DNA polymerase I, was discovered by Arthur Kornberg and his colleagues in 1956.[7][8][9] A 3’-5’ exonuclease proofreading function for DNA polymerases (E. coli) was first shown by Kornberg and Brutal.[10]  In 1976, Byrnes et. al. first purified eukaryotic Polδ complex from the rabbit erythroid hyperplastic bone marrow.[11] This was the third DNA polymerase discovered in mammalian cells. It was first described as a DNA polymerase that possessed an intrinsic 3’ to 5’ exonuclease activity. Following its purification from sources including calf thymus, human placenta, and HeLa cells [12][13][14][15][16], its activity was implicated in DNA repair.[17][18] Since its discovery as a polymerase, various laboratories have performed fidelity studies with purified Polδ complexes from S. cerevisiae [19][20] and S. pombe.[21] The human DNA polδ is a holoenzyme and a heterotetramer. The four subunits are: (POLD1/ p125), (POLD3/ p66), (POLD2/ p50) and 12 (POLD4/ p12), with the alternative names reflecting the molecular weights expressed in kilodaltons (kDa). Several groups independently cloned the human and murine cDNAs for the POLD1 catalytic subunit of Polδ.[4][22][23]

Gene

Polymerase delta 1, or POLD1 is the official gene symbol assigned by the HUGO (Human Genome Organisation) Gene Nomenclature Committee (HGNC).[24] POLD1 is also known as CDC2, MDPL, POLD, and CRCS10), is ~34 kb long and its cytogenetic location is chromosome 19.1 q13.33 21 A more precise location is from base pair 50,384,290 to base pair 50,418,018 on chromosome 19. [25][4][22][26] The mouse orthologue maps to mouse chromosome 7.[27] In humans, the major POLD1 transcript (NM_002691.3) contains 27 exons and translates into the p125 subunit or A unit of polδ.  A longer isoform has been reported with a 26 amino acid in-frame insertion after amino acid 592 (NP_001295561.1). A pseudogene (LOC100422453) has been reported on the long arm of chromosome 6.[25] Table 1 provides gene names and chromosomal locations for the various subunits of Polδ in humans, mice, budding yeast (S. cerevisiae) and fission yeast (S. pombe).

The POLD1 gene promoter is regulated via the cell cycle machinery and mRNA expression of POLD1 reaches a peak in late G1/S phase during DNA replication.[28] The POLD1 promoter is G/C-rich and has no TATA box. The transcription of this GC box-containing promoter is regulated by Sp1 and Sp1-related transcription factors such as Sp3, with their binding mediated via 11-bp repeat binding sequences.[29][30] The POLD1 promoter contains an E2F-like sequence located near the major transcription start site.[30] Another regulatory element, the cell cycle element/cell cycle genes homology region (CDE/CHR), located downstream of the start site is important for POLD1 transcription in G2/M phase by E2F1 and p21 proteins.[31][32] P53 regulates POLD1 transcription by indirect p21-dependent activation of a p53-p21-DREAM-CDE/CHR pathway.[33] One study has reported that the p53 tumor suppressor protein competes with Sp1 for binding to the POLD1 promoter.[29] A microRNA (miR), miR-155, downregulates POLD1 indirectly by suppressing the transcription factor FOXO3a[34], which has putative binding sites in the POLD1 promoter (RTMAAYA; response element).[35]

 Protein

P125 is the catalytic subunit of Polδ. Polδ possesses polymerase and exonuclease activity in the 3’-5’ direction. During DNA replication, Polδ associates with Replication Factor C (RFC) and PCNA for lagging strand synthesis.[36] Figure 1 provides a basic schematic of interactions during DNA replication.

Polδ uses a common B-family fold, similar to other DNA polymerases (Polα and ε).[37] Human POLD1/p125 has 2 putative zinc finger domains in the C-terminal region and a putative nuclear localization signal at the N-terminal end (residues 4-19).[4] 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 B-DNA polymerase family.[38] This domain has a beta hairpin structure that helps in active site switching to resolve nucleotide misincorporation. This domain also has 3 sequence motifs (ExoI, ExoII and ExoIII) that have a specific YX(3)D pattern at ExoIII. The active site has 4 conserved acidic residues (DEDD) that are required to bind metal ions for activity. These residues are D316 and E318 in the ExoI motif, D402 in the ExoII motif and D515 in the ExoIII motif. The Y511, DEDDy tyrosine residue in the ExoIII motif is required for catalysis.

The polymerase domain has motifs A and C, which are the most conserved motifs. These have 2 catalytic aspartates, 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 phosphodiester bond.

Tyrosine Y701 is involved in maintaining polymerase fidelity similar in function to tyrosine Y567 in the RB69 bacteriophage orthologue. This residue forms a steric gate that imparts selectivity to incorporate correct deoxyribonucleotides.[39] An LXCXE motif (711 to 715) mediates binding to pRB during the G1 phase of cell cycle.[40] The polymerase domain also has a highly conserved KKRY motif (residues 806 to 809) which is important for the binding and catalytic function.[41] POLD1 can be targeted to the nucleolus upon acidification via a nucleolar detention sequence (NoDS) motif.[42][43][44] The C-terminal domain has two conserved cysteine-rich metal-binding motifs (CysA and CysB) (from 1012 and 1083) required for PCNA binding and recruitment of accessory subunits respectively.[45][46]

Active POLD1 always forms a minimal heterotrimer with the POLD3/p66 subunit and the POLD2/p50[47] subunit, with the heterotrimer the dominantly active form following DNA damage or replication stress.[48] Under normal conditions of replication, these three subunits interact with a fourth POLD4/p12 subunit, which helps stabilize the complex.[49][50] 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.[51][52] Polδ heterotetramer reconstituted by coexpression of subunits in Sf9 cells had properties were similar to Polδ purified from the calf thymus, and the complete holoenzyme was very strongly stimulated by Proliferating Cell Nuclear Antigen (PCNA).[53] 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 Replication Factor C (RFC). The DNA Polδ holoenzyme is often considered to include PCNA and RFC as well as the four subunits of the polymerase complex. 

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[54] and [55]. A website at Vanderbilt University provides additional interaction on important POLD1 interactions.[56]

Expression and regulation

The POLD1/P125 protein is expressed ubiquitously across a panel of human tissues with high levels in the heart and lung tissues.[57] The subcellular localization of POLD1/p125 is predominantly in the nucleus and nucleoplasm.[58]

An age related reduction in POLD1/p125 has been observed in senescent human skin fibroblasts and in lymphocytes from an elderly population.[59][60] POLD1/p125 expression is epigenetically regulated in response to DNA damage.[61] Other studies have also shown that POLD1/p125 expression is regulated by miR-155 [34], p53[29] and by the long non-coding RNA, PVT1.[62] In the presence of DNA damage or replication stress (UV light, methyl methanesulfonate, hydroxyurea or aphidicolin), the POLD4/p12 subunit is rapidly degraded and a heterotrimer (Polδ3) without p12 is active.[48] The production of the heterotrimer depends on p12 degradation by RNF8, a protein involved in DSBs repair and possibly homologous recombination.[63] In addition, the E3 ligase CRL4Cdt2 can degrade POLD4/p12 during normal DNA replication and in the presence of DNA damage.[64] POLD4/p12 can also be degraded by the protease µ-calpain, that is involved in calcium-triggered apoptosis.[65][66]

POLD1/p125 has a NoDS domain that regulates transport to the nucleolus in response to acidosis.[44] This activity requires a direct interaction between the p50 subunit and the WRN protein.[67] During DNA damage response, WRN moves out of the nucleolus and thereby releases Polδ.[68][69] POLD1/p125 has also been shown to interact with PDIP46/SKAR[70] and LMO2.[71][72]

Function

DNA replication

DNA replication is a highly organized process that involves many enzymes and proteins, including several DNA polymerases. The major replicative activity in S phase of cell cycle depends on three DNA polymerases - Polymerase alpha (Polα), Polymerase delta (Polδ), and Polymerase epsilon (Polε). After initiation of DNA synthesis by Polα, Polδ or Polε execute lagging and leading strand synthesis, respectively.[73] These polymerases maintain a very high fidelity, which is ensured by Watson-Crick base pairing and 3'-exonuclease (or the proofreading) activity.[74] Polδ may synthesize the leading strand. [74][75][76][77][78] This is important as understanding and defining how these polymerases cooperate and function could impact the mutational landscape when they are defectiveMaintenance of replication fidelity is a fine balance between the unique errors by polymerases δ and ε [79], the equilibrium between proofreading and MMR, and distinction in ribonucleotide processing between the two strands.[80] Extensive studies in yeast models have shown that mutations in the exonuclease domain of Polδ and Polε homologues can cause a mutator phenotype.[81] 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 APOBEC mutations.[82] DNA-binding proteins that rapidly reassociate post-replication prevent Polδ from repairing errors produced by Polα in the mature lagging strand.[83] Yeast studies have shown that Polδ can proofread Polε errors on the leading strand.[84]

DNA Repair

POLD1 activity contributes to multiple evolutionarily conserved DNA repair processes, including Mismatch repair (MMR), Translesion synthesis (TLS), Base excision repair (BER), Nucleotide Excision repair (NER) and double-strand break (DSB) repair.[5] POLD1 mediates the post-incision steps in BER, NER and MMR.[5] An interaction between Polδ and MMR proofreading has been reported,[85] with cells bearing mutations that inactivate POLD1 and MMR components experiencing elevated mutation rates.[86][87] A Polδ heterotrimer (Polδ3) is active during the presence of DNA damage. Polδ3 is less error-prone than (Polδ4), and can discriminate better between mismatched pairs, and may prevent lesion bypass.[68][88] Polδ cooperates with Pol lambda (λ) in microhomology-mediated end joining (MMEJ).[89] The switch from Polδ to Polλ also supports the repair of oxidative DNA damage like 7,8-Dihydro-8-oxoguanine lesions.[90] Polδ polymerase switching to the specialized polymerase zeta (Polζ) is critical for TLS.[5] 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.[91]

Depletion of POLD1 can halt cell cycle at G1 and G2/M phases in human cells.[92] Cell cycle block in these phases typically indicates presence of DNA damage and activation of DNA damage checkpoints. POLD1 depleted cells are sensitive to inhibition of DNA damage checkpoint kinases ATR and CHK1.[93] In S. pombe, HR mechanisms can restart stalled replication forks by utilizing Polδ strand synthesis activity, but also that such nonallelic HR-mediated restart is very error prone potentially leading to increased genomic instability.[94] Polδ structurally and functionally interacts with the WRN protein, and WRN recruits Polδ to the nucleolus.[67] The WRN gene is mutated in Werner syndrome (an autosomal recessive disorder) leading to accelerated aging and increased genetic instability. The interaction with WRN increases the processivity of Polδ in a PCNA-independent manner.[95] Through these interactions WRN directly impacts DNA replication-repair and assists in Polδ-mediated synthesis.

Clinical significance

Cancer

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 Lynch syndrome (LS), which is characterized by the presence of microsatellite instability (MSI).[96] Germline mutations have been reported in the exonuclease domains of POLD1 and POLE, the catalytic subunit of Pole. These mutations are associated with oligo-adenomatous polyposis, early-onset colorectal cancer (CRC), endometrial cancer (EDMC), breast cancer, and brain tumors.([97][98][99][100][101], reviewed in[6]) Most of the reported POLD1 mutations linked to cancer are present in the exonuclease domain.[6][97][98][102][103][104] In contrast to LS, the POLD1 mutated tumors are microsatellite stable. Some data suggests the idea that POLD1 tumors are associated with driver mutations in genes including APC and KRAS.[97] The POLD1 missense mutation p. S478N, in the exonuclease domain, has been validated as damaging and pathogenic.[97] Other POLD1 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).[98][99][100]

In pediatric patients, double hit mutations in POLD1 or POLE and biallelic mismatch repair deficiency (bMMRD), leads to ultra-hypermutated tumor phenotypes.[105][106][107] Such phenotypes as ultra-hypermutation in tumors may indicate better response to newer cancer therapeutics in development, although this needs direct evaluation for POLD1. [108][109][110][111][112][113]. Bouffet et. al. report two siblings with bMMRD- glioblastoma multiforme who have somatic mutations in POLE  (P436H in one, S461P in the other), and showed a durable response to a clinical trial with the anti-programmed death-1 inhibitor nivolumab.  POLD1 mutations have been studied in cell lines [114][115][116][117] and mouse models.  For example, a homozygous Polδ mutation in mice that disrupts enzymatic function leads to highly elevated cancer incidence.[118]

MDPL

Missense heterozygous damaging mutations affecting POLD1 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).[57][119][120] This is a very rare syndrome, and few studies describing mutations have been reported. The mutations that have been observed are in the regions that affect the exonuclease domain and polymerase domains.[57][119] Five unrelated de novo cases have been described with the same heterozygous 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).[119] This variant is located in the highly conserved ExoIII domain and has not been completely characterized as yet.

Interestingly, POLD1 Ser605del and R507C variants have also been identified in a subset of patients with atypical Werner’s syndrome (AWS). These patients were reclassified as MPDL patients. MPDL, AWS and Werner’s syndrome all present with progeria.[121] A first example of germline transmission was observed in a mother and son with the Ser605del mutation.[122] Polδ is associated with lamins and the nuclear envelope during G1/S arrest or early S phase; mutations in lamins cause nuclear envelope-related lipodystrophies with phenotypes similar to MDPL and Werner’s syndrome.[123] Patients with homozygous splice variant in POLE1, the catalytic subunit of Pole, have a phenotype of facial dysmorphism, immunodeficiency, livedo, and short stature (also knowns as the FILS syndrome).[124]

In this context, it may be interesting that age-dependent downregulation of POLD1 has been observed.[60] 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 pathogenic focus on the idea of replication defects leading to genomic instability and checkpoint activation, ultimately leading to cell death or cellular senescence.

Cancer risk assessment and commercial testing

The hereditary colorectal cancers (CRCs) associated with mutations in the proofreading ability of POLD1 and POLE are sometimes termed as “polymerase proofreading associated polyposis” (PPAP), (although at least one study has identified POLD1 mutations associated with non-polyposis CRC).[97][98][100][102][103] POLD1 mutations have also been associated with an increased cancer predisposition of endometrial cancer.[97][100][101] Guidelines for genetic testing for POLD1 mutations which include: 1) Occurrence of 20-100 adenomas, and 2) Family history that meets the Amsterdam II criteria for colorectal and endometrial cancers.[99] Current clinical testing guidelines for families with mutations in POLD1/POLE include colonoscopies (every 1-2 years), gastroduodenoscopies (every 3 years) starting early (20-25), possibility for brain tumors and endometrial cancer screening (beginning at 40 for female carriers).[99] Currently studies are underway to determine the exact cancer risk from specific POLD1 mutations. Current data suggest that mutations in this gene are highly penetrant. Mutations affecting Pold and Pole mutations can co-occur along with MMR mutations.[106] This suggests panel gene testing should include MMR and Pol genes even in patients with MSI.

There are several options for commercial diagnostic testing for mutations in POLD1.[125] Genetic testing typically includes POLD1 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.[125] The availability of these genetic tests has opened up new possibilities for cancers previously classified as genetically undefined colorectal cancers or colorectal cancer type “X”.[101] Online resources for clinical testing for MDPL/MDP have also been developed.[126]

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Further reading

  • Kemper RR, Ahn ER, Zhang P, Lee MY, Rabin M (September 1992). "Human DNA polymerase delta gene maps to region 19q13.3-q13.4 by in situ hybridization". Genomics. 14 (1): 205–6. doi:10.1016/S0888-7543(05)80311-8. PMID 1427831.
  • Yang CL, Chang LS, Zhang P, Hao H, Zhu L, Toomey NL, Lee MY (February 1992). "Molecular cloning of the cDNA for the catalytic subunit of human DNA polymerase delta". Nucleic Acids Research. 20 (4): 735–45. doi:10.1093/nar/20.4.735. PMC 312012. PMID 1542570.
  • Popanda O, Thielmann HW (January 1992). "The function of DNA polymerases in DNA repair synthesis of ultraviolet-irradiated human fibroblasts". Biochimica et Biophysica Acta. 1129 (2): 155–60. doi:10.1016/0167-4781(92)90480-N. PMID 1730053.
  • Lee MY, Toomey NL (February 1987). "Human placental DNA polymerase delta: identification of a 170-kilodalton polypeptide by activity staining and immunoblotting". Biochemistry. 26 (4): 1076–85. doi:10.1021/bi00378a014. PMID 2436659.
  • Dresler SL, Gowans BJ, Robinson-Hill RM, Hunting DJ (August 1988). "Involvement of DNA polymerase delta in DNA repair synthesis in human fibroblasts at late times after ultraviolet irradiation". Biochemistry. 27 (17): 6379–83. doi:10.1021/bi00417a028. PMID 3146346.
  • Nishida C, Reinhard P, Linn S (January 1988). "DNA repair synthesis in human fibroblasts requires DNA polymerase delta". The Journal of Biological Chemistry. 263 (1): 501–10. PMID 3335506.
  • Hindges R, Hübscher U (August 1997). "Cloning, chromosomal localization, and interspecies interaction of mouse DNA polymerase delta small subunit (PolD2)". Genomics. 44 (1): 45–51. doi:10.1006/geno.1997.4838. PMID 9286699.
  • Wu SM, Zhang P, Zeng XR, Zhang SJ, Mo J, Li BQ, Lee MY (April 1998). "Characterization of the p125 subunit of human DNA polymerase delta and its deletion mutants. Interaction with cyclin-dependent kinase-cyclins". The Journal of Biological Chemistry. 273 (16): 9561–9. doi:10.1074/jbc.273.16.9561. PMID 9545286.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Coll JM, Hickey RJ, Cronkey EA, Jiang HY, Schnaper L, Lee MY, Uitto L, Syvaoja JE, Malkas LH (1998). "Mapping specific protein-protein interactions within the core component of the breast cell DNA synthesome". Oncology Research. 9 (11–12): 629–39. PMID 9563011.
  • Fox G, Popanda O, Thielmann HW (1998). "Evidence for reduced copying fidelity of DNA polymerases alpha, delta, and epsilon from Novikoff hepatoma cells". Journal of Cancer Research and Clinical Oncology. 123 (11–12): 659–68. doi:10.1007/s004320050121. PMID 9620226.
  • Kim ST, Lim DS, Canman CE, Kastan MB (December 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". The Journal of Biological Chemistry. 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. PMID 10608806.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Mo J, Liu L, Leon A, Mazloum N, Lee MY (June 2000). "Evidence that DNA polymerase delta isolated by immunoaffinity chromatography exhibits high-molecular weight characteristics and is associated with the KIAA0039 protein and RPA". Biochemistry. 39 (24): 7245–54. doi:10.1021/bi0000871. PMID 10852724.
  • Budworth H, Dianova II, Podust VN, Dianov GL (June 2002). "Repair of clustered DNA lesions. Sequence-specific inhibition of long-patch base excision repair be 8-oxoguanine". The Journal of Biological Chemistry. 277 (24): 21300–5. doi:10.1074/jbc.M201918200. PMID 11923315.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T (October 2002). "A proteomics approach to identify proliferating cell nuclear antigen (PCNA)-binding proteins in human cell lysates. Identification of the human CHL12/RFCs2-5 complex as a novel PCNA-binding protein". The Journal of Biological Chemistry. 277 (43): 40362–7. doi:10.1074/jbc.M206194200. PMID 12171929.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Smith RW, Nasheuer HP (September 2002). "Control of complex formation of DNA polymerase alpha-primase and cell-free DNA replication by the C-terminal amino acids of the largest subunit p180". FEBS Letters. 527 (1–3): 143–6. doi:10.1016/S0014-5793(02)03197-6. PMID 12220650.
  • Matheos D, Ruiz MT, Price GB, Zannis-Hadjopoulos M (October 2002). "Ku antigen, an origin-specific binding protein that associates with replication proteins, is required for mammalian DNA replication". Biochimica et Biophysica Acta. 1578 (1–3): 59–72. doi:10.1016/S0167-4781(02)00497-9. PMID 12393188.
  • Xie B, Mazloum N, Liu L, Rahmeh A, Li H, Lee MY (November 2002). "Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme". Biochemistry. 41 (44): 13133–42. doi:10.1021/bi0262707. PMID 12403614.
  • Shevelev IV, Ramadan K, Hübscher U (February 2002). "The TREX2 3'-->5' exonuclease physically interacts with DNA polymerase delta and increases its accuracy". TheScientificWorldJournal. 2: 275–81. doi:10.1100/tsw.2002.99. PMID 12806015.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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