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

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 cross-linking 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 approximately 9-fold in fancg 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.
Authors	Kazuhiko Yamamoto, Masamichi Ishiai, Nobuko Matsushita, Hiroshi Arakawa, Jane E Lamerdin, Jean-Marie Buerstedde, Mitsune Tanimoto, Mine Harada, Larry H Thompson, Minoru Takata
Journal	Molecular and cellular biology (Mol Cell Biol) Vol. 23 Issue 15 Pg. 5421-30 (Aug 2003) ISSN: 0270-7306 [Print] United States
PMID	12861027 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References	BRCA1 Protein BRCA2 Protein Cross-Linking Reagents DNA, Complementary DNA-Binding Proteins FANCG protein, human Fancg protein, mouse Fanconi Anemia Complementation Group G Protein Luminescent Proteins Green Fluorescent Proteins Mitomycin DNA Cisplatin
Topics	Amino Acid Sequence Animals BRCA1 Protein (metabolism) BRCA2 Protein (metabolism) Blotting, Western Cell Division Cell Line Cell Nucleus (metabolism) Chickens Chromosome Aberrations Cisplatin (pharmacology) Cloning, Molecular Cricetinae Cross-Linking Reagents (pharmacology) DNA (drug effects, radiation effects) DNA Damage DNA Repair DNA, Complementary (metabolism) DNA-Binding Proteins (metabolism, physiology) Dose-Response Relationship, Drug Dose-Response Relationship, Radiation Drug Resistance Fanconi Anemia Complementation Group G Protein Flow Cytometry Genetic Complementation Test Green Fluorescent Proteins Humans Luminescent Proteins (metabolism) Mice Mitomycin (pharmacology) Models, Genetic Molecular Sequence Data Mutation Plasmids (metabolism) Recombination, Genetic Reverse Transcriptase Polymerase Chain Reaction Sequence Homology, Amino Acid Time Factors X-Rays

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