Deletion of Brca2 exon 27 causes hypersensitivity to DNA crosslinks, chromosomal instability, and reduced life span in mice

Greg Donoho, Mark A. Brenneman, Tracy X. Cui, Dorit Donoviel, Hannes Vogel, Edwin H. Goodwin, David J. Chen, Paul Hasty

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Abstract

The Brca2 tumor-suppressor gene contributes to genomic stability, at least in part by a role in homologous recombinational repair. BRCA2 protein is presumed to function in homologous recombination through interactions with RAD51. Both exons 11 and 27 of Brca2 code for domains that interact with RAD51; exon 11 encodes eight BRC motifs, whereas exon 27 encodes a single, distinct interaction domain. Deletion of all RAD51-interacting domains causes embryonic lethality in mice. A less severe phenotype is seen with BRAC2 truncations that preserve some, but not all, of the BRC motifs. These mice can survive beyond weaning, but are runted and infertile, and die very young from cancer. Cells from such mice show hypersensitivity to some genotoxic agents and chromosomal instability. Here, we have analyzed mice and cells with a deletion of only the RAD51-interacting region encoded by exon 27. Mice homozygous for this mutation (called brca21ex1) have a shorter life span than that of control littermates, possibly because of early onsets of cancer and sepsis. No other phenotype was observed in these animals; therefore, the brca21ex1 mutation is less severe than truncations that delete some BRC motifs. However, at the cellular level, the brca21ex1 mutation causes reduced viability, hypersensitivity to the DNA interstrand crosslinking agent mitomycin C, and gross chromosomal instability, much like more severe truncations. Thus, the extreme carboxy-terminal region encoded by exon 27 is important for BRCA2 function, probably because it is required for a fully functional interaction between BRCA2 and RAD51.

Original languageEnglish (US)
Pages (from-to)317-331
Number of pages15
JournalGenes Chromosomes and Cancer
Volume36
Issue number4
DOIs
StatePublished - Apr 1 2003

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ASJC Scopus subject areas

  • Genetics
  • Cancer Research

Cite this

Donoho, G., Brenneman, M. A., Cui, T. X., Donoviel, D., Vogel, H., Goodwin, E. H., Chen, D. J., & Hasty, P. (2003). Deletion of Brca2 exon 27 causes hypersensitivity to DNA crosslinks, chromosomal instability, and reduced life span in mice. Genes Chromosomes and Cancer, 36(4), 317-331. https://doi.org/10.1002/gcc.10148