ATAD5 deficiency alters DNA damage metabolism and sensitizes cells to PARP inhibition

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F20%3A00535767" target="_blank" >RIV/68378050:_____/20:00535767 - isvavai.cz</a>

Result on the web

<a href="https://academic.oup.com/nar/article/48/9/4928/5820885" target="_blank" >https://academic.oup.com/nar/article/48/9/4928/5820885</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/nar/gkaa255" target="_blank" >10.1093/nar/gkaa255</a>

Result language

angličtina

Original language name

ATAD5 deficiency alters DNA damage metabolism and sensitizes cells to PARP inhibition

Original language description

Replication factor C (RFC), a heteropentamer of RFC1-5, loads PCNA onto DNA during replication and repair. Once DNA synthesis has ceased, PCNA must be unloaded. Recent findings assign the uloader role primarily to an RFC-like (RLC) complex, in which the largest RFC subunit, RFC1, has been replaced with ATAD5 (ELG1 in Saccharomyces cerevisiae). ATAD5-RLC appears to be indispensable, given that Atad5 knock-out leads to embryonic lethality. In order to learn how the retention of PCNA on DNA might interfere with normal DNA metabolism, we studied the response of ATAD5-depleted cells to several genotoxic agents. We show that ATAD5 deficiency leads to hypersensitivity to methyl methanesulphonate (MMS), camptothecin (CPT) and mitomycin C (MMC), agents that hinder the progression of replication forks. We further show that ATAD5-depleted cells are sensitive to poly(ADP)ribose polymerase (PARP) inhibitors and that the processing of spontaneous oxidative DNA damage contributes towards this sensitivity. We posit that PCNA molecules trapped on DNA interfere with the correct metabolism of arrested replication forks, phenotype reminiscent of defective homologous recombination (HR). As Atad5 heterozygous mice are cancer-prone and as ATAD5 mutations have been identified in breast and endometrial cancers, our finding may open a path towards the therapy of these tumours.

Czech name

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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

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OECD FORD branch

10601 - Cell biology

Project

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Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

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

Name of the periodical

Nucleic Acids Research

ISSN

0305-1048

e-ISSN

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Volume of the periodical

48

Issue of the periodical within the volume

9

Country of publishing house

GB - UNITED KINGDOM

Number of pages

12

Pages from-to

4928-4939

UT code for WoS article

000573914600030

EID of the result in the Scopus database

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