XRCC1 prevents toxic PARP1 trapping during DNA base excision repair

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F21%3A00544972" target="_blank" >RIV/68378050:_____/21:00544972 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.cell.com/molecular-cell/fulltext/S1097-2765(21)00366-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS109727652100366X%3Fshowall%3Dtrue" target="_blank" >https://www.cell.com/molecular-cell/fulltext/S1097-2765(21)00366-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS109727652100366X%3Fshowall%3Dtrue</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.molcel.2021.05.009" target="_blank" >10.1016/j.molcel.2021.05.009</a>

Jazyk výsledku

angličtina

Název v původním jazyce

XRCC1 prevents toxic PARP1 trapping during DNA base excision repair

Popis výsledku v původním jazyce

Mammalian DNA base excision repair (BER) is accelerated by poly(ADP-ribose) polymerases (PARPs) and the scaffold protein XRCC1. PARPs are sensors that detect single-strand break intermediates, but the critical role of XRCC1 during BER is unknown. Here, we show that protein complexes containing DNA polymerase beta and DNA ligase III that are assembled by XRCC1 prevent excessive engagement and activity of PARP1 during BER. As a result, PARP1 becomes ´trapped´ on BER intermediates in XRCC1-deficient cells in a manner similar to that induced by PARP inhibitors, including in patient fibroblasts from XRCC1-mutated disease. This excessive PARP1 engagement and trapping renders BER intermediates inaccessible to enzymes such as DNA polymerase beta and impedes their repair. Consequently, PARP1 deletion rescues BER and resistance to base damage in XRCC1(-/-) cells. These data reveal excessive PARP1 engagement during BER as a threat to genome integrity and identify XRCC1 as an ´anti-trapper´ that prevents toxic PARP1 activity.

Název v anglickém jazyce

XRCC1 prevents toxic PARP1 trapping during DNA base excision repair

Popis výsledku anglicky

Mammalian DNA base excision repair (BER) is accelerated by poly(ADP-ribose) polymerases (PARPs) and the scaffold protein XRCC1. PARPs are sensors that detect single-strand break intermediates, but the critical role of XRCC1 during BER is unknown. Here, we show that protein complexes containing DNA polymerase beta and DNA ligase III that are assembled by XRCC1 prevent excessive engagement and activity of PARP1 during BER. As a result, PARP1 becomes ´trapped´ on BER intermediates in XRCC1-deficient cells in a manner similar to that induced by PARP inhibitors, including in patient fibroblasts from XRCC1-mutated disease. This excessive PARP1 engagement and trapping renders BER intermediates inaccessible to enzymes such as DNA polymerase beta and impedes their repair. Consequently, PARP1 deletion rescues BER and resistance to base damage in XRCC1(-/-) cells. These data reveal excessive PARP1 engagement during BER as a threat to genome integrity and identify XRCC1 as an ´anti-trapper´ that prevents toxic PARP1 activity.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

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OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

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Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

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

Název periodika

Molecular Cell

ISSN

1097-2765

e-ISSN

1097-4164

Svazek periodika

81

Číslo periodika v rámci svazku

14

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

3018-3030

Kód UT WoS článku

000675833000005

EID výsledku v databázi Scopus

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