FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3

J. B. Wilson, K. Yamamoto, A. S. Marriott, S. Hussain, P. Sung, M. E. Hoatlin, C. G. Mathew, M. Takata, L. H. Thompson, G. M. Kupfer, N. J. Jones

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Fanconi anemia (FA) is a human disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinks and other damages. Thirteen complementation groups and genes are identified, including BRCA2, which is defective in the FA-D1 group. Eight of the FA proteins, including FANCG, participate in a nuclear core complex that is required for the monoubiquitylation of FANCD2 and FANCI. FANCD2, like FANCD1/BRCA2, is not part of the core complex, and we previously showed direct BRCA2-FANCD2 interaction using yeast two-hybrid analysis. We now show in human and hamster cells that expression of FANCG protein, but not the other core complex proteins, is required for co-precipitation of BRCA2 and FANCD2. We also show that phosphorylation of FANCG serine 7 is required for its co-precipitation with BRCA2, XRCC3 and FANCD2, as well as the direct interaction of BRCA2-FANCD2. These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3). Cells that fail to express either phospho-Ser7-FANCG, or full length BRCA2 protein, lack the interactions amongst the four component proteins. A role for D1-D2-G-X3 in homologous recombination repair (HRR) is supported by our finding that FANCG and the RAD51-paralog XRCC3 are epistatic for sensitivity to DNA crosslinking compounds in DT40 chicken cells. Our findings further define the intricate interface between FANC and HRR proteins in maintaining chromosome stability.

Original languageEnglish (US)
Pages (from-to)3641-3652
Number of pages12
JournalOncogene
Volume27
Issue number26
DOIs
StatePublished - Jun 12 2008
Externally publishedYes

Keywords

  • ATR
  • DNA repair
  • Epistasis
  • Fanconi anemia
  • Interstrand crosslinks
  • RAD51 paralog
  • Replication restart

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Wilson, J. B., Yamamoto, K., Marriott, A. S., Hussain, S., Sung, P., Hoatlin, M. E., Mathew, C. G., Takata, M., Thompson, L. H., Kupfer, G. M., & Jones, N. J. (2008). FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3. Oncogene, 27(26), 3641-3652. https://doi.org/10.1038/sj.onc.1211034