Journal
NUCLEIC ACIDS RESEARCH
Volume 42, Issue 12, Pages 7776-7792Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gku505
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Funding
- Centre National de la Recherche Scientifique, Universite de Strasbourg, Ligue contre le Cancer (comites du Bas-Rhin et du Haut-Rhin), Electricite de France, Agence Nationale de la Recherche [ANR-13-BSV8-0003-01]
- French government
- Science Foundation Ireland
- Association pour la Recherche Contre le Cancer
- LabEx Medalis and Agence Nationale de la Recherche
- LABEX [ANR-10-LABX-0034_Medalis]
- Agence Nationale de la Recherche (ANR) [ANR-13-BSV8-0003] Funding Source: Agence Nationale de la Recherche (ANR)
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Poly(ADP-ribosyl)ation is involved in numerous biological processes including DNA repair, transcription and cell death. Cellular levels of poly(ADP-ribose) (PAR) are regulated by PAR polymerases (PARPs) and the degrading enzyme PAR glycohydrolase (PARG), controlling the cell fate decision between life and death in response to DNA damage. Replication stress is a source of DNA damage, leading to transient stalling of replication forks or to their collapse followed by the generation of double-strand breaks (DSB). The involvement of PARP-1 in replicative stress response has been described, whereas the consequences of a deregulated PAR catabolism are not yet well established. Here, we show that PARG-deprived cells showed an enhanced sensitivity to the replication inhibitor hydroxyurea. PARG is dispensable to recover from transient replicative stress but is necessary to avoid massive PAR production upon prolonged replicative stress, conditions leading to fork collapse and DSB. Extensive PAR accumulation impairs replication protein A association with collapsed forks resulting in compromised DSB repair via homologous recombination. Our results highlight the critical role of PARG in tightly controlling PAR levels produced upon genotoxic stress to prevent the detrimental effects of PAR over-accumulation.
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