PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair.

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F24%3A00585313" target="_blank" >RIV/68378050:_____/24:00585313 - isvavai.cz</a>

Result on the web

<a href="https://www.embopress.org/doi/full/10.1038/s44318-024-00043-2" target="_blank" >https://www.embopress.org/doi/full/10.1038/s44318-024-00043-2</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s44318-024-00043-2" target="_blank" >10.1038/s44318-024-00043-2</a>

Result language

angličtina

Original language name

PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair.

Original language description

Targeting poly(ADP-ribose) glycohydrolase (PARG) is currently explored as a therapeutic approach to treat various cancer types, but we have a poor understanding of the specific genetic vulnerabilities that would make cancer cells susceptible to such a tailored therapy. Moreover, the identification of such vulnerabilities is of interest for targeting BRCA2,p53-deficient tumors that have acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) through loss of PARG expression. Here, by performing whole-genome CRISPR/Cas9 drop-out screens, we identify various genes involved in DNA repair to be essential for the survival of PARG,BRCA2,p53-deficient cells. In particular, our findings reveal EXO1 and FEN1 as major synthetic lethal interactors of PARG loss. We provide evidence for compromised replication fork progression, DNA single-strand break repair, and Okazaki fragment processing in PARG,BRCA2,p53-deficient cells, alterations that exacerbate the effects of EXO1/FEN1 inhibition and become lethal in this context. Since this sensitivity is dependent on BRCA2 defects, we propose to target EXO1/FEN1 in PARPi-resistant tumors that have lost PARG activity. Moreover, EXO1/FEN1 targeting may be a useful strategy for enhancing the effect of PARG inhibitors in homologous recombination-deficient tumors.

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

<a href="/en/project/GA22-00885S" target="_blank" >GA22-00885S: ADP-ribose metabolism and its role in neurological disease</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

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

Name of the periodical

EMBO Journal

ISSN

0261-4189

e-ISSN

1460-2075

Volume of the periodical

43

Issue of the periodical within the volume

6

Country of publishing house

US - UNITED STATES

Number of pages

28

Pages from-to

1015-1042

UT code for WoS article

001220428400008

EID of the result in the Scopus database

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