POLD1: Central mediator of DNA replication and repair, and implication in cancer and other pathologies

Abstract

The evolutionarily conserved human polymerase delta (POLD1) gene encodes the large p125 subunit which provides the essential catalytic activities of polymerase δ (Polδ), 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. Polδ function is essential for replication, with a primary role as the replicase for the lagging strand. Polδ 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. Polδ 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 Polδ with human pathologies. Mutations in Polδ 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 POLD1 function may also be altered in diabetes. We provide an overview of critical Polδ activities in the context of these pathologic conditions.

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

“…Hearing impairments constitute the most common features in MDPL syndrome, although they are not always found [14,15,17]. The POLD1 gene is expressed in all cells; therefore, the associated deafness may be a consequence of axonal neurons not functioning efficiently [27]. Among the female patients, only three patients had primary/secondary amenorrhea including our case [10,13,17], whereas the others reported a regular menstrual cycle.…”

“…Notably, our comparative analysis (Table 3) suggested that premature atherosclerosis with hypertension, cardiovascular diseases, and neoplasm might be less prevalent in MDPL compared with Werner syndrome [24] and other laminopathies [32]. Several germline mutations in POLD1 exonuclease domains are also known to predispose carriers to cancers, particularly colorectal and endometrial cancers [14,27]. However, to date at the age of 46 years, the patient has not presented any malignant disease.…”

“…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].…”

“…Moreover, the age-related decrease in POLD1 expression has been shown to be involved in the DNA repair pathway in vitro [29][30][31]. The mutation encoding p.Ser605del exists in a highly conserved region of the polymerase δ catalytic subunit, and leads to a failure to catalyze DNA polymerization [11,27]. In particular, a recombinant Ser605 deletion mutant exhibited loss of polymerase activity, but showed little loss of 3' to 5' exonuclease activity [11].…”

Sperm methylome alterations following yoga‐based lifestyle intervention in patients of primary male infertility: A pilot study

“…DNA hypomethylation was also observed at some key genes involved in male fertility, viz. GAMT (Schmidt et al, ) and TACC3 (Aitola, Sadek, Gustafsson, & Pelto‐Huikko, ) and at the DNA repair genes POLD1 (Nicolas, Golemis, & Arora, ) and EVL (Schultz et al, ) .…”