Parp-1 deficiency causes an increase of deletion mutations and insertions/rearrangements in vivo after treatment with an alkylating agent

Accumulated evidence suggests that Parp-1 is involved in DNA repair processes, including base excision repair, single-strand and double-strand break repairs. To understand the precise role of Parp-1 in genomic stability in vivo, we carried out mutation analysis using Parp-1 knockout (Parp-1^-/-) mice harboring two marker genes, gpt and fed/gam genes. Spontaneous mutant frequencies of both genes in the bone marrows and livers did not differ significantly between Parp-1^-/- and Parp-1^-/- mice (P > 0.05). After treatment with an alkylating agent, N-nitrosobis(2-hydroxypropyl) amine (BHP), the mutant frequency of the red/gam genes in the liver in Parp-1^-/- mice was 1.6-fold higher than that in Parp-1^+/+ mice (P < 0.05). Categorization of the mutations revealed that deletions larger than 1 kb or those accompanying 1-5 bp insertions at the deletion junctions, as well as rearrangements, were more frequently observed in Parp-1^-/- than in Parp-1^+/+ mice (P < 0.05, respectively). In contrast, mutant frequencies of the gpt gene in the livers of Parp-1^-/- and Parp-1^+/+ mice after BHP treatment were both elevated and there was no significant difference between the genotypes. These results indicate that Parp-1 is implicated in suppressing deletion mutations in vivo, especially those accompanying small insertions or rearrangements.