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

• Published in: Oncogene Vol. 24; no. 8; pp. 1328 - 1337
• Main Authors: SHIBATA, Atsushi, KAMADA, Nobuo, MASUMURA, Ken-Ichi, NOHMI, Takehiko, KOBAYASHI, Shizuko, TERAOKA, Hirobumi, NAKAGAMA, Hitoshi, SUGIMURA, Takashi, SUZUKI, Hiroshi, MASUTANI, Mitsuko
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 17.02.2005; Nature Publishing Group
• Subjects: Alkylating Agents - toxicity; Animals; Base excision repair; Biological and medical sciences; Bone Marrow - chemistry; Bone Marrow - metabolism; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chromosome aberrations; DNA Damage - genetics; DNA repair; DNA Repair - genetics; Double-strand break repair; Escherichia coli Proteins; Fundamental and applied biological sciences. Psychology; Gene deletion; Gene frequency; Genes; Genotypes; Kinases; Liver - chemistry; Liver - metabolism; Male; Medical genetics; Medical sciences; Mice; Mice, Knockout; Molecular and cellular biology; Mutagenesis, Insertional - genetics; Mutant frequency; Mutation; N-Nitrosobis(2-hydroxypropyl)amine; Nitrosamines - toxicity; Pentosyltransferases; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - deficiency; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - physiology; Proteins - genetics; Recombination, Genetic; Research centers; Sequence Deletion - genetics; Japan; Chromosomal aberration; Parp-1; recombination; Deficiency; gpt delta; Carcinogenesis; In vivo; mutation; Alkylating agent; Treatment; Insertion mutation; Deletion; rearrangement
• DOI: 10.1038/sj.onc.1208289
• ISSN: 0950-9232

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.