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

Oncogene volume 24, pages 1328–1337 (2005)Cite this article

Abstract

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.

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Acknowledgements

We appreciate the help and suggestions provided by M Tsutsumi in histopathological examinations and suggestions, and thank K Nakamoto, T Nozaki, and H Fujihara for technical assistance. We are grateful to M Yanagihara for maintenance of the animals. This work was supported in part by a Grant-in-Aid for the Second Term Comprehensive 10-Year Strategy for Cancer Control, and a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, and Culture of Japan (15025274).

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  1. Hiroshi Suzuki

    Present address: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan

Authors and Affiliations

  1. Biochemistry Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan

    Atsushi Shibata, Hitoshi Nakagama, Takashi Sugimura & Mitsuko Masutani

  2. Kyoritsu College of Pharmacy, Minato-ku, Tokyo, Japan

    Atsushi Shibata & Shizuko Kobayashi

  3. Medical Research Institute, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo, Japan

    Atsushi Shibata & Hirobumi Teraoka

  4. Chugai Pharmaceutical Co. Ltd, Gotemba, Shizuoka, Japan

    Nobuo Kamada & Hiroshi Suzuki

  5. Division of Genetics and Mutagenesis, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan

    Ken-ichi Masumura & Takehiko Nohmi

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  1. Atsushi Shibata
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Shibata, A., Kamada, N., Masumura, Ki. et al. Parp-1 deficiency causes an increase of deletion mutations and insertions/rearrangements in vivo after treatment with an alkylating agent. Oncogene 24, 1328–1337 (2005). https://doi.org/10.1038/sj.onc.1208289

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