FANCD1/BRCA2 Plays Predominant Role in the Repair of DNA Damage Induced by ACNU or TMZ

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

doi:10.1371/journal.pone.0019659

Title: FANCD1/BRCA2 Plays Predominant Role in the Repair of DNA Damage Induced by ACNU or TMZ

Journal Article · Mon May 09 00:00:00 EDT 2011 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0019659· OSTI ID:1627458

Kondo, Natsuko ^[1]; Takahashi, Akihisa ^[2]; Mori, Eiichiro ^[3]; Noda, Taichi ^[3]; Zdzienicka, Małgorzata Z. ^[4]; Thompson, Larry H. ^[5]; Helleday, Thomas ^[6]; Suzuki, Minoru ^[1]; Kinashi, Yuko ^[1]; Masunaga, Shinichiro ^[1]; Ono, Koji ^[1]; Hasegawa, Masatoshi ^[3]; Ohnishi, Takeo ^[7]

Kyoto University (Japan)
Gunma University (Japan)
Nara Medical University, Nara (Japan)
UMK Collegium Medicum, Bydgoszcz (Poland)
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Stockholm University (Sweden)
Nara Medical Univ., Nara (Japan)

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.

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Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); Ministry of Education, Culture, Sports, Science and Technology of Japan; Central Research Institute of the Electric Power Industry; Japan Space Forum

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1627458

Journal Information:: PLoS ONE, Vol. 6, Issue 5; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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