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2016 ; 590
(1
): 128-41
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POLD1: Central mediator of DNA replication and repair, and implication in cancer
and other pathologies
#MMPMID27320729
Nicolas E
; Golemis EA
; Arora S
Gene
2016[Sep]; 590
(1
): 128-41
PMID27320729
show ga
The evolutionarily conserved human polymerase delta (POLD1) gene encodes the
large p125 subunit which provides the essential catalytic activities of
polymerase ? (Pol?), 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. Pol? function is essential for replication,
with a primary role as the replicase for the lagging strand. Pol? 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. Pol? 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 Pol? with human pathologies. Mutations in Pol? 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 Pol? activities in the context of these
pathologic conditions.
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