International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


Pittman D
Medical College of Ohio

Co-Authors: 1) Smiraldo P, 1) Gruver A, 1) Osborn J, 2) Miller K, 2) Albala J, 3) Tarsounas M, 3) Claas A, 3) West S
Institutions: 1) Medical College of Ohio, 2) Lawrence Livermore National Laboratory, 3) Cancer Research UK, London Research Institute

A large part of biology is defined by the reshuffling of genomes. Chromosome rearrangements are origins for genetic variation, speciation, and immunological diversity. Yet, genome instability is a cancer-initiating event and errors during meiosis cause syndromes and infertility. Homologous recombination is a pathway for maintaining genomic stability and is directed primarily by the Rad51 gene family. We currently focus our attention on Rad51d. Embryos deficient for Rad51d died midway through gestation, and lethality was partially bypassed by introducing an additional disruption in the Trp53 tumor suppressor gene. At the cellular level, Rad51d deficient mouse embryo fibroblast (MEF) cells were hypersensitive to DNA damaging agents, failed to recruit the Rad51 protein to sites of DNA damage, and exhibited gross chromosomal instability. Moreover, the Rad51d protein localizes to telomeres of meiotic and mitotic cells. Elevated anaphase bridges and end-to-end mitotic chromosome fusions in MEF cells indicated direct involvement of Rad51d in telomere maintenance. Additionally, inhibition of Rad51d synthesis by RNA interference in human cell lines resulted in increased telomere fusions. Patterns of protein interactions within the context of the Rad51 family show evidence for the existence of a single large complex and several smaller complexes. Preliminary data suggest ATPase activity of Rad51d directs interactions within these protein complexes. Our studies will determine how the repair of DNA damage and prevention of telomere fusions by homologous recombination mechanisms maintain the structure of the mammalian genome.

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