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 red/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.
Shibata
Atsushi
A
Biochemistry Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Kamada
Nobuo
N
Masumura
Ken-Ichi
K
Nohmi
Takehiko
T
Kobayashi
Shizuko
S
Teraoka
Hirobumi
H
Nakagama
Hitoshi
H
Sugimura
Takashi
T
Suzuki
Hiroshi
H
Masutani
Mitsuko
M
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D001853:Bone Marrow / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D029968:Escherichia coli Proteins; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional / Q000235:genetics*; D009602:Nitrosamines / Q000633:toxicity; D010430:Pentosyltransferases; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000235:genetics; D011995:Recombination, Genetic; D017384:Sequence Deletion / Q000235:genetics*
D000477:Alkylating Agents; D029968:Escherichia coli Proteins; D009602:Nitrosamines; D011506:Proteins; C012457:diisopropanolnitrosamine; D010430:Pentosyltransferases; C071962:Gpt protein, E coli; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases