FANCD1/BRCA2 plays predominant role in the repair of DNA damage induced by ACNU or TMZ

• Published in: PloS one Vol. 6; no. 5; p. e19659
• Main Authors: Kondo, Natsuko, Takahashi, Akihisa, Mori, Eiichiro, Noda, Taichi, Zdzienicka, Małgorzata Z, Thompson, Larry H, Helleday, Thomas, Suzuki, Minoru, Kinashi, Yuko, Masunaga, Shinichiro, Ono, Koji, Hasegawa, Masatoshi, Ohnishi, Takeo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.05.2011; Public Library of Science (PLoS)
• Subjects: Alkylating agents; Alkylation; Anemia; Animals; BASIC BIOLOGICAL SCIENCES; Biology; BRCA2 protein; BRCA2 Protein - metabolism; Breast cancer; Cancer therapies; Cell Line; Cell survival; Chemical compounds; chemotherapeutic agent; Chemotherapy; cross-linking; Crosslinking; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Damage; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; DNA methylation; DNA repair; DNA Repair - drug effects; DNA Repair - genetics; Down-Regulation - drug effects; Embryo fibroblasts; Embryos; FANCC protein; Fanconi Anemia - genetics; Fanconi syndrome; Fanconi's anemia; Fibroblasts; Gene Silencing - drug effects; Genetic research; Genomes; Glioblastoma; Glioblastoma - metabolism; Glioblastoma - pathology; glioblastoma multiforme; Glioma; Gliomas; Health aspects; Humans; Laboratories; Lungs; Medicine; Mice; Models, Biological; Mutation; Nimustine - pharmacology; Oncology; Pharmacology; Proteins; Rad51 Recombinase - metabolism; Recombination, Genetic - drug effects; Recombination, Genetic - genetics; Repair; Ribonucleic acid; RNA; RNA, Small Interfering - metabolism; RNA-mediated interference; Sensitivity; Sensitivity enhancement; siRNA; small interfering RNA; Temozolomide; transfection; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0019659

Nimustine (ACNU) and temozolomide (TMZ) are DNA alkylating agents which are commonly used in chemotherapy for glioblastomas. ACNU is a DNA cross-linking agent and TMZ is a methylating agent. The therapeutic efficacy of these agents is limited by the development of resistance. In this work, the role of the Fanconi anemia (FA) repair pathway for DNA damage induced by ACNU or TMZ was examined. Cultured mouse embryonic fibroblasts were used: FANCA(-/-), FANCC(-/-), FANCA(-/-)C(-/-), FANCD2(-/-) cells and their parental cells, and Chinese hamster ovary and lung fibroblast cells were used: FANCD1/BRCA2mt, FANCG(-/-) and their parental cells. Cell survival was examined after a 3 h ACNU or TMZ treatment by using colony formation assays. All FA repair pathways were involved in ACNU-induced DNA damage. However, FANCG and FANCD1/BRCA2 played notably important roles in the repair of TMZ-induced DNA damage. The most effective molecular target correlating with cellular sensitivity to both ACNU and TMZ was FANCD1/BRCA2. In addition, it was found that FANCD1/BRCA2 small interference RNA efficiently enhanced cellular sensitivity toward ACNU and TMZ in human glioblastoma A172 cells. These findings suggest that the down-regulation of FANCD1/BRCA2 might be an effective strategy to increase cellular chemo-sensitization towards ACNU and TMZ.