Depletion of the 110-kilodalton isoform of poly(ADP-ribose) glycohydrolase increases sensitivity to genotoxic and endotoxic stress in mice.
Poly(ADP-ribosylation) is rapidly stimulated in cells following DNA damage. This posttranslational modification is regulated by the synthesizing enzyme poly(ADP-ribose) polymerase 1 (PARP-1) and the degrading enzyme poly(ADP-ribose) glycohydrolase (PARG). Although the role of PARP-1 in response to DNA damage has been studied extensively, the function of PARG and the impact of poly(ADP-ribose) homeostasis in various cellular processes are largely unknown. Here we show that by gene targeting in embryonic stem cells and mice, we specifically deleted the 110-kDa PARG protein (PARG(110)) normally found in the nucleus and that depletion of PARG(110) severely compromised the automodification of PARP-1 in vivo. PARG(110)-deficient mice were viable and fertile, but these mice were hypersensitive to alkylating agents and ionizing radiation. In addition, these mice were susceptible to streptozotocin-induced diabetes and endotoxic shock. These data indicate that PARG(110) plays an important role in DNA damage responses and in pathological processes.
Cortes
Ulrich
U
International Agency for Research on Cancer, 69008 Lyon, France.
Tong
Wei-Min
WM
Coyle
Donna L
DL
Meyer-Ficca
Mirella L
ML
Meyer
Ralph G
RG
Petrilli
Virginie
V
Herceg
Zdenko
Z
Jacobson
Elaine L
EL
Jacobson
Myron K
MK
Wang
Zhao-Qi
ZQ
D000477:Alkylating Agents / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D003921:Diabetes Mellitus, Experimental; D004198:Disease Susceptibility; D005260:Female; D005720:Gamma Rays; D018390:Gene Targeting; D006026:Glycoside Hydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D008770:Methylnitrosourea / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism*; D012772:Shock, Septic; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D015996:Survival Rate
D000477:Alkylating Agents; D008070:Lipopolysaccharides; D020033:Protein Isoforms; D008770:Methylnitrosourea; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase