The response of Parp knockout mice against DNA damaging agents.
Gene-disruption studies involving poly(ADP-ribose) polymerase (Parp) have identified the various roles of Parp in cellular responses to DNA damage. The partial rescue of V[D]J recombination process in SCID/Parp(-/-) double mutant mice indicates the participation of Parp in the repair of DNA strand break. Parp(-/-) mice are more sensitive to the lethal effects of alkylating agents. Parp is also thought to be involved in base-excision repair after DNA damage caused by alkylating agents. On the other hand, resistance of Parp(-/-) mice to DNA damage induced by reactive oxygen species implicates the contribution of Parp to cell death through NAD depletion. Parp(-/-) mice with two different genetic backgrounds also show enhanced sensitivity to the lethal effects of gamma-irradiation. Parp(-/-) mice show more severe villous atrophy of the small intestine compared to the wild-type counterpart in a genetic background of 129Sv/C57BL6. Other forms of enhanced tissue damage have been identified in Parp(-/-) mice with a genetic background of 129Sv/ICR. For example, Parp(-/-) mice exhibit extensive hemorrhage in the glandular stomach and other tissues, such as the testes, after gamma-irradiation. Severe myelosuppression is also observed in both Parp(+/+) and Parp(-/-) mice, but Parp(+/+) mice show extensive extramedullary hematopoiesis in the spleen during the recovery phase of post-irradiation, whereas the spleen of Parp(-/-) mice exhibits severe atrophy with no extramedullary hematopoiesis. The absence of extramedullary hematopoiesis in the spleen is probably the underlying mechanism of hemorrhagic tendency in various tissues of Parp(-/-) mice. These findings suggest that loss of Parp activity could contribute to post-irradiation tissue hemorrhage.
Masutani
M
M
Biochemistry Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo, 104-0045, Japan. mmasutan@gan2.ncc.go.jp
Nozaki
T
T
Nakamoto
K
K
Nakagama
H
H
Suzuki
H
H
Kusuoka
O
O
Tsutsumi
M
M
Sugimura
T
T
D000477:Alkylating Agents / Q000008:administration & dosage*; D000818:Animals; D016923:Cell Death; D004247:DNA / Q000187:drug effects* / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D005753:Gastric Mucosa / Q000378:metabolism; D008297:Male; D008741:Methyl Methanesulfonate / Q000008:administration & dosage; D008770:Methylnitrosourea / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016513:Mice, SCID; D009154:Mutation; D009243:NAD / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000502:physiology; D013154:Spleen / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D013270:Stomach / Q000473:pathology / Q000528:radiation effects; D016019:Survival Analysis; D013737:Testis / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects
D000477:Alkylating Agents; D009243:NAD; D008770:Methylnitrosourea; D004247:DNA; D008741:Methyl Methanesulfonate; D011065:Poly(ADP-ribose) Polymerases