title: PARG is dispensable for recovery from transient replicative stress but required to prevent detrimental accumulation of poly(ADP-ribose) upon prolonged replicative stress.
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.
authors.affiliation: Biotechnology and Cell Signalling, UMR7242 CNRS, Université de Strasbourg, IREBS, Laboratory of Excellence Medalis, Equipe Labellisée Ligue contre le Cancer, ESBS, 300 Blvd Sébastien Brant, CS 10413, 67412 Illkirch, France.
authors.forename: Giuditta
authors.initials: G
authors.lastname: Illuzzi
authors.affiliation: Biotechnology and Cell Signalling, UMR7242 CNRS, Université de Strasbourg, IREBS, Laboratory of Excellence Medalis, Equipe Labellisée Ligue contre le Cancer, ESBS, 300 Blvd Sébastien Brant, CS 10413, 67412 Illkirch, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Fouquerel
authors.affiliation: Biotechnology and Cell Signalling, UMR7242 CNRS, Université de Strasbourg, IREBS, Laboratory of Excellence Medalis, Equipe Labellisée Ligue contre le Cancer, ESBS, 300 Blvd Sébastien Brant, CS 10413, 67412 Illkirch, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Amé
authors.affiliation: Biotechnology and Cell Signalling, UMR7242 CNRS, Université de Strasbourg, IREBS, Laboratory of Excellence Medalis, Equipe Labellisée Ligue contre le Cancer, ESBS, 300 Blvd Sébastien Brant, CS 10413, 67412 Illkirch, France.
authors.forename: Aurélia
authors.initials: A
authors.lastname: Noll
authors.affiliation: Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland.
authors.forename: Kristina
authors.initials: K
authors.lastname: Rehmet
authors.affiliation: Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland.
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Nasheuer
authors.affiliation: Biotechnology and Cell Signalling, UMR7242 CNRS, Université de Strasbourg, IREBS, Laboratory of Excellence Medalis, Equipe Labellisée Ligue contre le Cancer, ESBS, 300 Blvd Sébastien Brant, CS 10413, 67412 Illkirch, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Dantzer
authors.affiliation: Biotechnology and Cell Signalling, UMR7242 CNRS, Université de Strasbourg, IREBS, Laboratory of Excellence Medalis, Equipe Labellisée Ligue contre le Cancer, ESBS, 300 Blvd Sébastien Brant, CS 10413, 67412 Illkirch, France valerie.schreiber@unistra.fr.
authors.forename: Valérie
authors.initials: V
authors.lastname: Schreiber
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D004277:DNA, Single-Stranded / Q000032:analysis; D006026:Glycoside Hydrolases / Q000502:physiology*; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D010766:Phosphorylation; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D059767:Recombinational DNA Repair; D051716:Replication Protein A / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D059807:S Phase Cell Cycle Checkpoints; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D002843:Chromatin; D004277:DNA, Single-Stranded; D006657:Histones; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051716:Replication Protein A; D011064:Poly Adenosine Diphosphate Ribose; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase; D006918:Hydroxyurea