Fanconi anemia FANCG protein in mitigating radiation- and enzyme-induced DNA double-strand breaks by homologous recombination in vertebrate cells

Kazuhiko Yamamoto, Masamichi Ishiai, Nobuko Matsushita, Hiroshi Arakawa, Jane E. Lamerdin, Jean Marie Buerstedde, Mitsune Tanimoto, Mine Harada, Larry H. Thompson, Minoru Takata

Research output: Contribution to journalArticle

126 Scopus citations

Abstract

The rare hereditary disorder Fanconi anemia (FA) is characterized by progressive bone marrow failure, congenital skeletal abnormality, elevated susceptibility to cancer, and cellular hypersensitivity to DNA crosslinking chemicals and sometimes other DNA-damaging agents. Molecular cloning identified six causative genes (FANCA, -C, -D2, -E, -F, and -G) encoding a multiprotein complex whose precise biochemical function remains elusive. Recent studies implicate this complex in DNA damage responses that are linked to the breast cancer susceptibility proteins BRCA1 and BRCA2. Mutations in BRCA2, which participates in homologous recombination (HR), are the underlying cause in some FA patients. To elucidate the roles of FA genes in HR, we disrupted the FANCG/XRCC9 locus in the chicken B-cell line DT40. FANCG-deficient DT40 cells resemble mammalian fancg mutants in that they are sensitive to killing by cisplatin and mitomycin C (MMC) and exhibit increased MMC and radiation-induced chromosome breakage. We find that the repair of I-SceI-induced chromosomal double-strand breaks (DSBs) by HR is decreased ∼9-fold infancg cells compared with the parental and FANCG-complemented cells. In addition, the efficiency of gene targeting is mildly decreased in FANCG-deficient cells, but depends on the specific locus. We conclude that FANCG is required for efficient HR-mediated repair of at least some types of DSBs.

Original languageEnglish (US)
Pages (from-to)5421-5430
Number of pages10
JournalMolecular and Cellular Biology
Volume23
Issue number15
DOIs
StatePublished - Aug 2003
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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    Yamamoto, K., Ishiai, M., Matsushita, N., Arakawa, H., Lamerdin, J. E., Buerstedde, J. M., Tanimoto, M., Harada, M., Thompson, L. H., & Takata, M. (2003). Fanconi anemia FANCG protein in mitigating radiation- and enzyme-induced DNA double-strand breaks by homologous recombination in vertebrate cells. Molecular and Cellular Biology, 23(15), 5421-5430. https://doi.org/10.1128/MCB.23.15.5421-5430.2003