title: FANCD1/BRCA2 plays predominant role in the repair of DNA damage induced by ACNU or TMZ.
abstract: 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.
authors.affiliation: Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Osaka, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Kondo
authors.forename: Akihisa
authors.initials: A
authors.lastname: Takahashi
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Mori
authors.forename: Taichi
authors.initials: T
authors.lastname: Noda
authors.forename: Małgorzata Z
authors.initials: MZ
authors.lastname: Zdzienicka
authors.forename: Larry H
authors.initials: LH
authors.lastname: Thompson
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.forename: Minoru
authors.initials: M
authors.lastname: Suzuki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kinashi
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Masunaga
authors.forename: Koji
authors.initials: K
authors.lastname: Ono
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Takeo
authors.initials: T
authors.lastname: Ohnishi
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005199:Fanconi Anemia / Q000235:genetics; D020868:Gene Silencing / Q000187:drug effects; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008954:Models, Biological; D015376:Nimustine / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism; D011995:Recombination, Genetic / Q000187:drug effects / Q000235:genetics; D000077204:Temozolomide
chemical_list: D024682:BRCA2 Protein; D034741:RNA, Small Interfering; D015376:Nimustine; D003606:Dacarbazine; D051135:Rad51 Recombinase; D000077204:Temozolomide