title: Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality.
abstract: The metabolism of poly(ADP-ribose) (PAR) is critical for genomic stability in multicellular eukaryotes. Here, we show that the failure to degrade PAR by means of disruption of the murine poly(ADP-ribose) glycohydrolase (PARG) gene unexpectedly causes early embryonic lethality and enhanced sensitivity to genotoxic stress. This lethality results from the failure to hydrolyze PAR, because PARG null embryonic day (E) 3.5 blastocysts accumulate PAR and concurrently undergo apoptosis. Moreover, embryonic trophoblast stem cell lines established from early PARG null embryos are viable only when cultured in medium containing the poly(ADP-ribose) polymerase inhibitor benzamide. Cells lacking PARG also show reduced growth, accumulation of PAR, and increased sensitivity to cytotoxicity induced by N-methyl-N'-nitro-N-nitrosoguanidine and menadione after benzamide withdrawal. These results provide compelling evidence that the failure to degrade PAR has deleterious consequences. Further, they define a role for PARG in embryonic development and a protective role in the response to genotoxic stress.
authors.affiliation: Institute for Cell Engineering and Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Koh
authors.forename: Ann M
authors.initials: AM
authors.lastname: Lawler
authors.forename: Marc F
authors.initials: MF
authors.lastname: Poitras
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sasaki
authors.forename: Sigrid
authors.initials: S
authors.lastname: Wattler
authors.forename: Michael C
authors.initials: MC
authors.lastname: Nehls
authors.forename: Tobias
authors.initials: T
authors.lastname: Stöger
authors.forename: Guy G
authors.initials: GG
authors.lastname: Poirier
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
mesh_terms: D000818:Animals; D017209:Apoptosis; D001755:Blastocyst / Q000166:cytology / Q000378:metabolism; D049109:Cell Proliferation; D020964:Embryo Loss / Q000139:chemically induced* / Q000196:embryology / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D006026:Glycoside Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011247:Pregnancy; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism; D024483:Vitamin K 3 / Q000494:pharmacology / Q000633:toxicity
chemical_list: D008769:Methylnitronitrosoguanidine; D011064:Poly Adenosine Diphosphate Ribose; D024483:Vitamin K 3; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase