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POLD1: Central mediator of DNA replication and repair, and implication in cancer and other pathologies
Gene. 2016 Jun 16;590(1) :128-141
PMID: 27320729    PMCID: PMC4969162    URL: http://www.ncbi.nlm.nih.gov/pubmed/27320729
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Abstract
The evolutionarily conserved human polymerase delta (POLD1) gene encodes the large p125 subunit which provides the essential catalytic activities of polymerase delta (Poldelta), mediated by 5'-3' DNA polymerase and 3'-5' exonuclease moieties. POLD1 associates with three smaller subunits (POLD2, POLD3, POLD4), which together with Replication Factor C and Proliferating Nuclear Cell Antigen constitute the polymerase holoenzyme. Poldelta function is essential for replication, with a primary role as the replicase for the lagging strand. Poldelta also has an important proofreading ability conferred by the exonuclease activity, which is critical for ensuring replicative fidelity, but also serves to repair DNA lesions arising as a result of exposure to mutagens. Poldelta has been shown to be important for multiple forms of DNA repair, including nucleotide excision repair, double strand break repair, base excision repair, and mismatch repair. A growing number of studies in the past decade have linked germline and sporadic mutations in POLD1 and the other subunits of Poldelta with human pathologies. Mutations in Poldelta in mice and humans lead to genomic instability, mutator phenotype and tumorigenesis. The advent of genome sequencing techniques has identified damaging mutations in the proofreading domain of POLD1 as the underlying cause of some inherited cancers, and suggested that mutations in POLD1 may influence therapeutic management. In addition, mutations in POLD1 have been identified in the developmental disorders of mandibular hypoplasia, deafness, progeroid features and lipodystrophy and atypical Werner syndrome, while changes in expression or activity of POLD1 have been linked to senescence and aging. Intriguingly, some recent evidence suggests that POLD1 function may also be altered in diabetes. We provide an overview of critical Poldelta activities in the context of these pathologic conditions.
Notes
Nicolas, Emmanuelle Golemis, Erica A Arora, Sanjeevani REVIEW Gene. 2016 Jun 16;590(1):128-141. doi: 10.1016/j.gene.2016.06.031.