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DNA polymerase α-primase facilitates PARP inhibitor-induced fork acceleration and protects BRCA1-deficient cells against ssDNA gaps
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DNA polymerase α-primase facilitates PARP inhibitor-induced fork acceleration and protects BRCA1-deficient cells against ssDNA gaps
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Journal Article
DNA polymerase α-primase facilitates PARP inhibitor-induced fork acceleration and protects BRCA1-deficient cells against ssDNA gaps
2024
Overview
PARP inhibitors (PARPi), known for their ability to induce replication gaps and accelerate replication forks, have become potent agents in anticancer therapy. However, the molecular mechanism underlying PARPi-induced fork acceleration has remained elusive. Here, we show that the first PARPi-induced effect on DNA replication is an increased replication fork rate, followed by a secondary reduction in origin activity. Through the systematic knockdown of human DNA polymerases, we identify POLA1 as mediator of PARPi-induced fork acceleration. This acceleration depends on both DNA polymerase α and primase activities. Additionally, the depletion of POLA1 increases the accumulation of replication gaps induced by PARP inhibition, sensitizing cells to PARPi. BRCA1-depleted cells are especially susceptible to the formation of replication gaps under POLA1 inhibition. Accordingly, BRCA1 deficiency sensitizes cells to POLA1 inhibition. Thus, our findings establish the POLA complex as important player in PARPi-induced fork acceleration and provide evidence that lagging strand synthesis represents a targetable vulnerability in BRCA1-deficient cells.
PARP inhibitors are effective anticancer agents that induce replication gaps and accelerate replication forks. Here, the authors reveal that DNA polymerase α / primase complex is a mediator of PARP inhibitor-induced replication fork acceleration particularly BRCA1-deficient cells.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 13/109
/ 13/89
/ 14/63
/ 38/22
/ 42
/ 64
/ 692/4017
/ 96
/ Cancer
/ DNA
/ DNA Replication - drug effects
/ DNA, Single-Stranded - genetics
/ DNA, Single-Stranded - metabolism
/ DNA-Directed DNA Polymerase - genetics
/ DNA-Directed DNA Polymerase - metabolism
/ Humanities and Social Sciences
/ Humans
/ Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
/ Primase
/ Science
