Alternative titles; symbols
HGNC Approved Gene Symbol: POLD2
Cytogenetic location: 7p13 Genomic coordinates (GRCh38): 7:44,114,680-44,124,325 (from NCBI)
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 (see 102579), and the 4 subunit polymerase complex: POLD1 (174761), POLD2, POLD3 (611415), and POLD4 (611525) (Liu and Warbrick, 2006).
Zhang et al. (1995) cloned and sequenced full-length cDNAs of bovine and human POLD2. The predicted bovine and human polypeptides of 50.9 and 51.3 kD, respectively, are 94% identical, similar to the identity of the bovine and human catalytic POLD1 subunits. The high degree of conservation of the polypeptides suggested an essential function for the small subunit in the heterodimeric core enzyme. Searches of protein databases failed to detect significant homology with any protein sequenced to that point.
By PCR analysis of DNA from a panel of human/hamster hybrid cell lines, Zhang et al. (1995) mapped the POLD2 gene to chromosome 7.
Stumpf (2021) mapped the POLD2 gene to chromosome 7p13 based on an alignment of the POLD2 sequence (GenBank BC000459) with the genomic sequence (GRCh38).
Associations Pending Confirmation
For discussion of a possible association between a syndromic combined immunodeficiency disorder and variation in the POLD2 gene, see 600815.0001.
This variant is classified as a variant of unknown significance because its contribution to a syndromic combined immunodeficiency disorder has not been confirmed.
In a 17-year-old male (patient 1), born of consanguineous parents, with a syndromic combined immunodeficiency disorder, Conde et al. (2019) identified a homozygous mutation in the POLD2 gene resulting in an asp293-to-asn (D293N) substitution in the phosphodiesterase domain of the protein. The variant, which was found by exome sequencing, was absent from the ExAC and 1000 Genomes Project databases. Peripheral blood mononuclear cells from the patient showed reduced stability of the variant POLD2 protein, as well as decreased expression of other POLD components. Immunoprecipitation studies showed impaired interactions of the D293N variant with POLD1 (174761) and POLD3 (611415), suggesting decreased stability of the overall polymerase-delta complex. The D293N variant showed normal polymerase activity in vitro, suggesting that decreased protein stability was responsible for impaired polymerase function. Patient-derived T cells showed reduced proliferative responses to stimuli as well as decreased progression through the cell cycle compared to controls. Detailed analysis of patient fibroblasts showed evidence of a DNA replication defect associated with replication stress, disturbed dynamics of the replication fork, and the presence of replication-associated DNA lesions. DNA repair capacity in response to genotoxic reagents was normal, suggesting a specific defect in mitotic DNA synthesis. Overexpression of wildtype POLD2 rescued the defects in vitro. The patient presented in infancy with recurrent respiratory infections leading to bronchiectasis. He also had chronic molluscum contagiosum-associated facial lesions and recurrent skin abscesses. Other features included short stature, severely impaired intellectual development with poor speech, attention deficits, and hyperactivity. Immunologic workup showed low levels of CD4+ T cells, B cells, and NK cells.
Conde, C. D., Petronczki, O. Y., Baris, S., Willmann, K. L., Girardi, E., Salzer, E., Weitzer, S., Ardy, R. C., Krolo, A., Ijspeert, H., Kiykim, A., Karakoc-Aydiner, E., and 9 others. Polymerase delta deficiency causes syndromic immunodeficiency with replicative stress. J. Clin. Invest. 129: 4194-4206, 2019. [PubMed: 31449058] [Full Text: https://doi.org/10.1172/JCI128903]
Liu, G., Warbrick, E. The p66 and p12 subunits of DNA polymerase delta are modified by ubiquitin and ubiquitin-like proteins. Biochem. Biophys. Res. Commun. 349: 360-366, 2006. [PubMed: 16934752] [Full Text: https://doi.org/10.1016/j.bbrc.2006.08.049]
Ng, L., Tan, C.-K., Downey, K. M., Fisher, P. A. Enzymologic mechanism of calf thymus DNA polymerase delta. J. Biol. Chem. 266: 11699-11704, 1991. [PubMed: 2050671]
Stumpf, A. M. Personal Communication. Baltimore, Md. 05/21/2021.
Zhang, J., Tan, C.-K., McMullen, B., Downey, K. M., So, A. G. Cloning of the cDNAs for the small subunits of bovine and human DNA polymerase delta and chromosomal location of the human gene (POLD2). Genomics 29: 179-186, 1995. [PubMed: 8530069] [Full Text: https://doi.org/10.1006/geno.1995.1229]