Fanconi Anemia FANCG Protein in Mitigating Radiation- and Enzyme-Induced DNA Double-Strand Breaks by Homologous Recombination in Vertebrate Cells
Open Access
- 1 August 2003
- journal article
- research article
- Published by Informa UK Limited in Molecular and Cellular Biology
- Vol. 23 (15), 5421-5430
- https://doi.org/10.1128/mcb.23.15.5421-5430.2003
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 ∼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.Keywords
This publication has 67 references indexed in Scilit:
- Insights into DNA recombination from the structure of a RAD51–BRCA2 complexNature, 2002
- Recombination at Double-Strand Breaks and DNA EndsMolecular Cell, 2001
- Genetic Analysis of the DNA-dependent Protein Kinase Reveals an Inhibitory Role of Ku in Late S–G2 Phase DNA Double-strand Break RepairJournal of Biological Chemistry, 2001
- Fanconi Anemia Proteins Localize to Chromatin and the Nuclear Matrix in a DNA Damage- and Cell Cycle-regulated MannerPublished by Elsevier BV ,2001
- Foci on FanconiTrends in Molecular Medicine, 2001
- Role of BRCA2 in Control of the RAD51 Recombination and DNA Repair ProteinMolecular Cell, 2001
- Reverse genetic studies of homologous DNA recombination using the chicken B–lymphocyte line, DT40Philosophical Transactions Of The Royal Society B-Biological Sciences, 2001
- Spectrum of mutations in the Fanconi anaemia group G gene, FANCG/XRCC9European Journal of Human Genetics, 2000
- BRCA1 deficient embryonic stem cells display a decreased homologous recombination frequency and an increased frequency of non-homologous recombination that is corrected by expression of a Brca1 transgeneOncogene, 1999
- G2 chromosomal radiosensitivity in Fanconi's anemiaMutation Research, 1979