Functional interplay between BRCA2/FancD1 and FancC in DNA repair

Hiroyuki Kitao, Kazuhiko Yamamoto, Nobuko Matsushita, Mioko Ohzeki, Masamichi Ishiai, Minoru Takata

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Abstract

A rare hereditary disorder, Fanconi anemia (FA), is caused by mutations in an array of genes, which interact in a common FA pathway/network. These genes encode components of the FA "core" complex, a key factor FancD2, the familial breast cancer suppressor BRCA2/FancD1, and Brip1/FancJ helicase. Although BRCA2 is known to play a pivotal role in homologous recombination repair by regulating Rad51 recombinase, the precise functional relationship between BRCA2 and the other FA genes is unclear. Here we show that BRCA2-dependent chromatin loading of Rad51 after mitomycin C treatment was not compromised by disruption of FANCC or FANCD2. Rad51 and FancD2 form colocalizing subnuclear foci independently of each other. Furthermore, we created a conditional BRCA2 truncating mutation lacking the C-terminal conserved domain (CTD) (brca2ΔCTD), and disrupted the FANCC gene in this background. The fancc/ brca2ΔCTD double mutant revealed an epistatic relationship between FANCC and BRCA2 CTD in terms of x-ray sensitivity. In contrast, levels of cisplatin sensitivity and mitomycin C-induced chromosomal aberrations were increased in fancc/brca2ΔCTD cells relative to either single mutant. Taken together, these results indicate that FA proteins work together with BRCA2/Rad51-mediated homologous recombination in double strand break repair, whereas the FA pathway plays a role that is independent of the CTD of BRCA2 in interstrand cross-link repair. These results provide insights in to the functional interplay between the classical FA pathway and BRCA2.

Original languageEnglish
Pages (from-to)21312-21320
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number30
DOIs
Publication statusPublished - Jul 28 2006
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kitao, H., Yamamoto, K., Matsushita, N., Ohzeki, M., Ishiai, M., & Takata, M. (2006). Functional interplay between BRCA2/FancD1 and FancC in DNA repair. Journal of Biological Chemistry, 281(30), 21312-21320. https://doi.org/10.1074/jbc.M603290200