DNA polymerase delta in dna replication and genome maintenance

Abstract

The eukaryotic genome is in a constant state of modification and repair. Faithful transmission of the genomic information from parent to daughter cells depends upon an extensive system of surveillance, signaling, and DNA repair, as well as accurate synthesis of DNA during replication. Often, replicative synthesis occurs over regions of DNA that have not yet been repaired, presenting further challenges to genomic stability. DNA polymerase δ (Pol δ) occupies a central role in all of these processes: catalyzing the accurate replication of a majority of the genome, participating in several DNA repair synthetic pathways, and contributing structurally to the accurate bypass of problematic lesions during translesion synthesis. The concerted actions of pol δ on the lagging strand, pol ε on the leading strand, associated replicative factors, and the mismatch repair (MMR) proteins results in a mutation rate of less than one misincorporation per genome per replication cycle. This low mutation rate provides a high level of protection against genetic defects during development and may prevent the initiation of malignancies in somatic cells. This review explores the role of Pol δ in replication fidelity and genome maintenance.

The tail that wags the dog: p12, the smallest subunit of DNA polymerase δ, is degraded by ubiquitin ligases in response to DNA damage and during cell cycle progression

“…7,8 In addition, Pol δ also participates in gap-filling processes in DNA repair. 1,3 Pol δ from budding yeast is a 3-subunit enzyme that has been well studied. 9 In human cells, Pol δ4 is a heterotetramer of the p125, p50, and p68 subunits, which are paralogs of their yeast counterparts, together with a fourth subunit, p12.…”

The second subunit of DNA-polymerase delta is required for genomic stability and epigenetic regulation

“…Pol d is a highly accurate DNA polymerase that is essential for DNA replication, repair, and recombination and thus for genome integrity (Prindle and Loeb, 2012). Dysfunction of Pol d results in genomic instability and cancer (Church et al, 2013;Palles et al, 2013).…”

“…Dysfunction of Pol d results in genomic instability and cancer (Church et al, 2013;Palles et al, 2013). Pol d in mammals consists of four subunits: the catalytic subunit p125 (POLD1, corresponding to Pol3p in yeast (Saccharomyces cerevisiae) and CDC6 in Saccharomyces pombe); the accessory subunit p50 (POLD2, corresponding to Pol31p in S. cerevisiae and CDC1 in S. pombe); p68 (POLD3, corresponding to Pol32p in S. cerevisiae and CDC27 in S. pombe); and the smallest subunit p12 (POLD4, corresponding to CDM1 in S. pombe; Prindle and Loeb, 2012). The Pol31p and Pol32p subunits in yeast also interact with DNA polymerase zeta (Pol z) to participate in DNA translesion synthesis and mutagenesis (Johnson et al, 2012).…”

Definitive diagnosis of mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome caused by a recurrent <i>de novo</i> mutation in the <i>POLD1</i> gene

“…The POLD1 gene belongs to the protein family of human DNA polymerase delta and encodes the p125 catalytic subunit. It plays a critical role in genome maintenance through its involvement in replicative DNA synthesis and multiple synthetic repair processes [27,28]. POLD1 cooperates with WRN, which a gene that is typically associated with Werner syndrome [25,29].…”