PARG is dispensable for recovery from transient replicative stress but required to prevent detrimental accumulation of poly(ADP-ribose) upon prolonged replicative stress

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Title: PARG is dispensable for recovery from transient replicative stress but required to prevent detrimental accumulation of poly(ADP-ribose) upon prolonged replicative stress
Authors: Illuzzi, Giuditta
Fouquerel, Elise
Amé, Jean-Christophe
Noll, Aurélia
Rehmet, Kristina
Nasheuer, Heinz-Peter
Dantzer, Françoise
Schreiber, Valérie
Permanent link: http://hdl.handle.net/10197/9161
Date: 8-Jul-2014
Abstract: Poly(ADP-ribosyl)ation is involved in numerous bio-logical 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.
Funding Details: Science Foundation Ireland
Type of material: Journal Article
Publisher: Oxford University Press
Journal: Nucleic Acids Research
Volume: 42
Issue: 12
Start page: 7776
End page: 7792
Copyright (published version): 2014 the Authors
Keywords: PARGTransient replicative stresspoly(ADP-ribose)Prolonged replicative stressPoly(ADP-ribosyl)ationPARPsCell fate decisionsPAR
DOI: 10.1093/nar/gku505
Language: en
Status of Item: Peer reviewed
Appears in Collections:SBI Research Collection

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