DNA polymerase α-primase facilitates PARP inhibitor-induced fork acceleration and protects BRCA1-deficient cells against ssDNA gaps

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F24%3A73626752" target="_blank" >RIV/61989592:15110/24:73626752 - isvavai.cz</a>

Result on the web

<a href="https://www.nature.com/articles/s41467-024-51667-1" target="_blank" >https://www.nature.com/articles/s41467-024-51667-1</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41467-024-51667-1" target="_blank" >10.1038/s41467-024-51667-1</a>

Result language

angličtina

Original language name

DNA polymerase α-primase facilitates PARP inhibitor-induced fork acceleration and protects BRCA1-deficient cells against ssDNA gaps

Original language description

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 alpha 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 alpha / primase complex is a mediator of PARP inhibitor-induced replication fork acceleration particularly BRCA1-deficient cells.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10608 - Biochemistry and molecular biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Nature Communications

ISSN

2041-1723

e-ISSN

2041-1723

Volume of the periodical

15

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

11

Pages from-to

7375

UT code for WoS article

001300255000036

EID of the result in the Scopus database

2-s2.0-85202190366