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.
International Agency for Research on Cancer, 69008 Lyon, France.
Ulrich
U
Cortes
Wei-Min
WM
Tong
Donna L
DL
Coyle
Mirella L
ML
Meyer-Ficca
Ralph G
RG
Meyer
Virginie
V
Petrilli
Zdenko
Z
Herceg
Elaine L
EL
Jacobson
Myron K
MK
Jacobson
Zhao-Qi
ZQ
Wang
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