Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease.
Poly(ADP-ribosyl)ation is catalyzed by NAD+: protein(ADP-ribosyl) transferase (ADPRT), a chromatin-associated enzyme which, in the presence of DNA breaks, transfers ADP-ribose from NAD+ to nuclear proteins. This post-translational modification has been implicated in many fundamental processes, like DNA repair, chromatin stability, cell proliferation, and cell death. To elucidate the biological function of ADPRT and poly(ADP-ribosyl)ation in vivo the gene was inactivated in the mouse germ line. Mice homozygous for the ADPRT mutation are healthy and fertile. Analysis of mutant tissues and fibroblasts isolated from mutant fetuses revealed the absence of ADPRT enzymatic activity and poly(ADP-ribose), implying that no poly(ADP-ribosyl)ated proteins are present. Mutant embryonic fibroblasts were able to efficiently repair DNA damaged by UV and alkylating agents. However, proliferation of mutant primary fibroblasts as well as thymocytes following gamma-radiation in vivo was impaired. Moreover, mutant mice are susceptible to the spontaneous development of skin disease as approximately 30% of older mice develop epidermal hyperplasia. The generation of viable ADPRT-/-mice negates an essential role for this enzyme in normal chromatin function, but the impaired proliferation and the onset of skin lesions in older mice suggest a function for ADPRT in response to environmental stress.
Wang
Z Q
ZQ
Research Institute of Molecular Pathology (IMP), Vienna, Austria.
Auer
B
B
Stingl
L
L
Berghammer
H
H
Haidacher
D
D
Schweiger
M
M
Wagner
E F
EF
D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D002678:Chimera; D004260:DNA Repair / Q000502:physiology; D004198:Disease Susceptibility; D004817:Epidermis / Q000473:pathology; D005333:Fetus / Q000201:enzymology; D005347:Fibroblasts / Q000502:physiology*; D005720:Gamma Rays; D018095:Germ-Line Mutation; D006965:Hyperplasia; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011064:Poly Adenosine Diphosphate Ribose / Q000032:analysis / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D012871:Skin Diseases / Q000209:etiology*; D013950:Thymus Gland / Q000166:cytology / Q000528:radiation effects
D012333:RNA, Messenger; D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases