PARENT SESSION
9:00 AM to 11:00 AM
Sunday, April 21, 2002
Symposium 4
Genes Affecting Radiosensitivity and Genomic Instability: From Yeast to Man
Room: Crystal Ballroom 1-2
Chair: Brown, J. Martin ¹¹Stanford University, Stanford, CA
Speakers: Nickloff, Jac²; Brown, J. Martin¹; Thompson, Larry⁴²University of New Mexico School of Medicine, Albuquerque, NM¹Stanford University, Stanford, CA⁴1069 Felicia Ct., Livermore, CA, US

(S04-4) The function of XRCC2 and other RAD51-like genes in homologous recombination and genetic stability.

Thacker, John^*,1, Deans, Bryan¹, Griffin, Carol¹, O'Regan, Paul¹, Spink, Karen¹, ¹ MRC Radiation & Genome Stability Unit, Harwell, Oxfordshire, U.K.

ABSTRACT-
Radiation damage can be repaired by several different pathways, but the influence of repair by homologous recombination (HRR) has only recently been highlighted. In eukaryotes the RAD51 protein is central to the DNA pairing and strand invasion steps of HRR. We and others have recently identified several novel mammalian RAD51-like proteins, including XRCC2, XRCC3, RAD51L1, RAD51L2 and RAD51L3. These proteins are highly conserved in mammalian species and we have shown that XRCC2 interacts physically with RAD51L3 (Braybrooke et al. 2000 J. Biol. Chem. 275:29100-29106). We also have established a functional link between XRCC2 and RAD51 by showing that radiation-induced RAD51 focus formation is severely impaired in the XRCC2-deficient cells (O'Regan et al. 2001 J. Biol. Chem., 276, 22148-22153). Cells lacking XRCC2 or XRCC3 were found to have high levels of chromosome mis-segregation, associated with fragmentation of the centrosome in mitosis (Griffin et al. 2000 Nature Cell Biol. 2:757-761). We have disrupted the Xrcc2 gene in mice, but found that this gave embryonic lethality. Embryos are radiation sensitive and surprisingly have severe neurological defects (Deans et al. 2000, EMBO J., 24:6675-6685). Mouse embryonic fibroblasts deficient in XRCC2 can be cultured but show high levels of genetic instability. These studies indicate that XRCC2 and other RAD51-like proteins have important roles in both endogenous and radiation damage repair, and by analogy to other proteins associated with HRR (such as the breast-cancer predisposing proteins, BRCA1 and BRCA2) may have a role in cancer prevention.

KEYWORDS: homologous recombination, XRCC2, RAD51-like genes, mouse knockout