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POLD1
DNA polymerase delta catalytic subunit (DPOD1) is an enzyme that is encoded in the human by the POLD1 gene, in the DNA polymerase delta complex. DPOD1 is responsible for synthesizing the lagging strand of DNA, and has also been implicated in some activities at the leading strand (Figure 1). The DPOD1 subunit encodes both DNA polymerizing and exonuclease 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 POLD1 defects is the result of increased base substitutions or due to fork collapse and production of DNA double strand breaks (DSBs). Recent reviews have addressed important functions of POLD1.
The first DNA polymerase, DNA polymerase I, was discovered by Arthur Kornberg 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 hyperplastic 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 (E. coli) had first been described 4 years earlier by Kornberg and Brutlag, reviewed in. The human DNA Polδ is a heterotetramer. The four subunits are: (POLD1/ p125), (POLD3/ p66), (POLD2/ p50) and (POLD4/ p12), with the alternative names reflecting the molecular weights expressed in kilodaltons (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.
Polymerase (DNA) delta 1, catalytic subunit and POLD1 are the name and gene symbol approved by the Human Genome Organization (HUGO) Gene Nomenclature Committee (HGNC). POLD1 is also known as CDC2, MDPL, POLD, and CRCS10), 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 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 pseudogene (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 (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. 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. The POLD1 promoter contains an E2F-like sequence located near the major transcription start site. 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. P53 regulates POLD1 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 POLD1 promoter. A microRNA (miR), miR-155, downregulates POLD1 indirectly by suppressing the transcription factor FOXO3a, which has putative binding sites in the POLD1 promoter (RTMAAYA; response element).
POLD1/p125 has a common B-family fold, similar to other DNA polymerases (Polα and ε). Human POLD1/p125 has a putative nuclear localization signal at the N-terminal 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 B-DNA polymerase family. This domain has a beta hairpin structure that helps in switching between the polymerase and exonuclease active sites in case of nucleotide misincorporation.
Motifs A and C, which are the most conserved of the polymerase domain. 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 functions similarly to tyrosine Y567 in the RB69 bacteriophage orthologue as the sugar steric gate that prevents ribonucleotide incorporation. An LXCXE motif (711 to 715) mediates binding to pRB during the G1 phase 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 nucleolus upon acidification via a nucleolar detention sequence (NoDS) motif represented by small sequence motifs dispersed throughout the protein coding region. The C-terminal domain has two conserved cysteine-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 [4Fe-4S] 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-MMS19, which interacts with the apoprotein to ensure specific Fe-S cluster insertion.
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POLD1
DNA polymerase delta catalytic subunit (DPOD1) is an enzyme that is encoded in the human by the POLD1 gene, in the DNA polymerase delta complex. DPOD1 is responsible for synthesizing the lagging strand of DNA, and has also been implicated in some activities at the leading strand (Figure 1). The DPOD1 subunit encodes both DNA polymerizing and exonuclease 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 POLD1 defects is the result of increased base substitutions or due to fork collapse and production of DNA double strand breaks (DSBs). Recent reviews have addressed important functions of POLD1.
The first DNA polymerase, DNA polymerase I, was discovered by Arthur Kornberg 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 hyperplastic 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 (E. coli) had first been described 4 years earlier by Kornberg and Brutlag, reviewed in. The human DNA Polδ is a heterotetramer. The four subunits are: (POLD1/ p125), (POLD3/ p66), (POLD2/ p50) and (POLD4/ p12), with the alternative names reflecting the molecular weights expressed in kilodaltons (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.
Polymerase (DNA) delta 1, catalytic subunit and POLD1 are the name and gene symbol approved by the Human Genome Organization (HUGO) Gene Nomenclature Committee (HGNC). POLD1 is also known as CDC2, MDPL, POLD, and CRCS10), 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 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 pseudogene (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 (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. 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. The POLD1 promoter contains an E2F-like sequence located near the major transcription start site. 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. P53 regulates POLD1 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 POLD1 promoter. A microRNA (miR), miR-155, downregulates POLD1 indirectly by suppressing the transcription factor FOXO3a, which has putative binding sites in the POLD1 promoter (RTMAAYA; response element).
POLD1/p125 has a common B-family fold, similar to other DNA polymerases (Polα and ε). Human POLD1/p125 has a putative nuclear localization signal at the N-terminal 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 B-DNA polymerase family. This domain has a beta hairpin structure that helps in switching between the polymerase and exonuclease active sites in case of nucleotide misincorporation.
Motifs A and C, which are the most conserved of the polymerase domain. 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 functions similarly to tyrosine Y567 in the RB69 bacteriophage orthologue as the sugar steric gate that prevents ribonucleotide incorporation. An LXCXE motif (711 to 715) mediates binding to pRB during the G1 phase 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 nucleolus upon acidification via a nucleolar detention sequence (NoDS) motif represented by small sequence motifs dispersed throughout the protein coding region. The C-terminal domain has two conserved cysteine-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 [4Fe-4S] 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-MMS19, which interacts with the apoprotein to ensure specific Fe-S cluster insertion.