Peer-Reviewed Journal Details
Mandatory Fields
Illuzzi, G, Fouquerel, E, Ame, JC, Noll, A, Rehmet, K, Nasheuer, HP, Dantzer, F, Schreiber, V
2014
December
Nucleic Acids Research
PARG is dispensable for recovery from transient replicative stress but required to prevent detrimental accumulation of poly(ADP-ribose) upon prolonged replicative stress
Published
Altmetric: 2WOS: 31 ()
Optional Fields
DEPENDENT PROTEIN-KINASE MOUSE ES CELLS STRAND BREAK FORMATION DNA END RESECTION HOMOLOGOUS RECOMBINATION CHECKPOINT ACTIVATION IONIZING-RADIATION GENOTOXIC STRESS DAMAGE SITES S-PHASE
42
7776
7792
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.
10.1093/nar/gku505
Grant Details
Publication Themes
Biomedical Science and Engineering