International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


D Pittman
Medical College of Ohio

Smiraldo P, Gruver A
Medical College of Ohio

Genomic integrity is regularly challenged by DNA damage.  Homologous recombination repair (HRR) is an error-free repair pathway that utilizes homologous DNA as a replication template during the repair of DNA double strand breaks (DSBs) and interstrand crosslinks. The strand invasion step during HRR requires Rad51, a homolog of the E. coli RecA protein, and six Rad51 paralogs—Rad51b, Rad51c, Rad51d, Xrcc2, Xrcc3, and Dmc1. We are investigating the role of the Rad51 paralogs in mice, and this presentation will focus on the Rad51d gene. A homozygous Rad51d disruption conferred embryo lethality midway through gestation.  Phenotypes suggest that mutant cells undergo suboptimal repair of DNA damage, presumably DSBs, resulting in chromosomal rearrangements and cell death. To determine whether a mutation in the tumor suppressor gene Trp53 circumvents cell cycle checkpoint mechanisms, embryos deficient for Rad51d and Trp53 were generated. The double-mutants survived five days longer than Rad51d-/- embryos, and a wide range of mutant phenotypes included developmental delay, blood islands, and exencephaly. Consistent with Rad51d being involved in DNA damage repair, fibroblast cells cultured from the mutant embryos were highly sensitive to mitomycin C and methyl methanesulfonate, moderately sensitive to X-rays, and mildly sensitive to ultraviolet light. In addition, Rad51 foci formed after treatment with irradiation are smaller and four to six fold fewer than in controls, suggesting that Rad51d is necessary for recruiting Rad51 to the sites of DNA damage. These studies are helping determine the role of Rad51d in HRR and in maintaining the integrity of the mammalian genome.

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