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POLYMERASE (DNA-DIRECTED), DELTA 3, ACCESSORY SUBUNIT; POLD3

POLYMERASE (DNA-DIRECTED), DELTA 3, ACCESSORY SUBUNIT; POLD3

Alternative titles; symbolsKIAA0039P66HGNC Approved Gene Symbol: POLD3Cytogenetic location: 11q13.4 Genomic coordinates (GRCh38): 11:74,592,581-74,669,340 (f...

Alternative titles; symbols

  • KIAA0039
  • P66

HGNC Approved Gene Symbol: POLD3

Cytogenetic location: 11q13.4 Genomic coordinates (GRCh38): 11:74,592,581-74,669,340 (from NCBI)

▼ Description
The DNA polymerase delta complex is involved in DNA replication and repair, and it consists of the proliferating cell nuclear antigen (PCNA; 176740), the multisubunit replication factor C (RFC; see 102579), and the 4 subunit polymerase complex: POLD1 (174761), POLD2 (600815), POLD3, and POLD4 (611525) (Liu and Warbrick, 2006).

▼ Cloning and Expression
By sequencing clones obtained from a size-fractionated human immature myeloid cell line cDNA library, Nomura et al. (1994) cloned POLD3, which they designated KIAA0039. The deduced protein contains 491 amino acids. Northern blot analysis detected high expression in lung, kidney, testis, and colon, moderate expression in placenta, skeletal muscle, and ovary, and low expression in heart, brain, liver, pancreas, spleen, thymus, prostate, small intestine, and peripheral blood leukocytes.

Using KIAA0039 and 5-prime extension of HeLa cell total RNA, Hughes et al. (1999) confirmed the cloning of POLD3, which they called p66. The protein has a calculated molecular mass of 51.4 kD but migrates as a 66-kD protein. It contains a proline-rich region, a C-terminal PCNA-binding domain, and a bipartite nuclear localization signal.

▼ Gene Function
Using PCNA-affinity chromatography and glycerol gradient centrifugation of partially purified fractions of mouse mammary tumor cells, Hughes et al. (1999) obtained complexes of DNA polymerase delta and DNA ligase I (see 126391) and found that both contained Pold3.

Liu and Warbrick (2006) showed that both the p12 (POLD4) and p66 subunits can be modified by ubiquitin in predominantly monoubiquitinated forms. The p66 subunit was specifically sumoylated by SUMO3 (602231) on lys258 and lys433.

Mayle et al. (2015) showed that broken fork repair initially uses error-prone Pol32/POLD3-dependent synthesis, but that mutagenic synthesis is limited to within a few kilobases from the break by Mus81 (606591) endonuclease and a converging fork. Mus81 suppresses template switches between both homologous sequences and diverged human Alu repetitive elements, highlighting its importance for stability of highly repetitive genomes. Mayle et al. (2015) proposed that lack of a timely converging fork or Mus81 may propel genome instability observed in cancer.

The MUS81-EME1 (610885) structure-specific endonuclease promotes the appearance of chromosome gaps or breaks at common fragile sites (CFSs) following replicative stress. Minocherhomji et al. (2015) showed that entry of cells into mitotic prophase triggers the recruitment of MUS81 to CFSs. The nuclease activity of MUS81 then promotes POLD3-dependent DNA synthesis at CFSs, which serves to minimize chromosome missegregation and nondisjunction. Minocherhomji et al. (2015) proposed that the attempted condensation of incompletely duplicated loci in early mitosis serves as the trigger for completion of DNA replication at CFS loci in human cells. Given that this POLD3-dependent mitotic DNA synthesis is enhanced in aneuploid cancer cells that exhibit intrinsically high levels of chromosomal instability (CIN+) and replicative stress, the authors suggested that targeting this pathway could represent a novel therapeutic approach.

Dilley et al. (2016) defined break-induced telomere synthesis and showed that it utilizes a specialized replisome, which underlies alternate lengthening of telomeres (ALT) maintenance. DNA double-strand breaks enact nascent telomere synthesis by long-tract unidirectional replication. PCNA loading by RFC acts as the initial sensor of telomere damage to establish predominance of DNA polymerase delta through its POLD3 subunit. Break-induced telomere synthesis requires the RFC-PCNA-Pol-delta axis, but is independent of other canonical replisome components, ATM (607585) and ATR (601215), or the homologous recombination protein RAD51 (179617).

▼ Mapping
Stumpf (2021) mapped the POLD3 gene to chromosome 11q13.4 based on an alignment of the POLD3 sequence (GenBank BC108909) with the genomic sequence (GRCh38).

Tags: 11q13.4