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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

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OECD FORD obor

10601 - Cell biology

Projekt

<a href="/cs/project/GA22-00885S" target="_blank" >GA22-00885S: Metabolismus ADP-ribózy a jeho role v neurologických onemocněních</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

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

Název periodika

EMBO Journal

ISSN

0261-4189

e-ISSN

1460-2075

Svazek periodika

43

Číslo periodika v rámci svazku

6

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

28

Strana od-do

1015-1042

Kód UT WoS článku

001220428400008

EID výsledku v databázi Scopus

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