Role of Parp-1 in suppressing spontaneous deletion mutation in the liver and brain of mice at adolescence and advanced age

Abstract Poly(ADP-ribose) polymerase-1 knockout ( Parp-1 −/− ) mice show increased frequency of spontaneous liver tumors compared to wild-type mice after aging. To understand the impact of Parp-1 deficiency on mutations during aging, in this study, we analyzed spontaneous mutations in Parp-1 −/− aged mice. Parp-1 −/− mice showed tendencies of higher mutation frequencies of the red/gam genes at 18 months of age, compared to Parp-1 +/+ mice, in the liver and brain. Complex-type deletions, accompanying small insertion were observed only in Parp-1 −/− mice in the liver and brain. Further analysis in the liver showed that the frequency of single base deletion mutations at non-repeat or short repeat sequences was 5.8-fold higher in Parp-1 −/− than in Parp-1 +/+ mice ( p Parp-1 −/− mice compared to Parp-1 +/+ mice ( p  = 0.084). These results support the model that Parp-1 is involved in suppressing imprecise repair of endogenous DNA damage leading to deletion mutation during aging. The mutation frequencies of the gpt gene in the brain were found to be 3-fold lower in Parp-1 −/− than in Parp-1 +/+ mice at 4 months of age ( p gpt mutation showed an increase at 18 months of age in the Parp-1 −/− ( p Parp-1 +/+ brains, suggesting that Parp-1 deficiency causes an increase of point mutations in the brain by aging.