ROLES OF MRELL AND RAD50 IN THE DNA DAMAGE RESPONSE

University Of Wisconsin Madison, Madison WI

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Abstract

DESCRIPTION: The S. cerevisiae RAD52 epistasis group gene products mediate recombinational DNA repair, and are therefore important for the repair of ionizing radiation induced DNA damage in yeast. These proteins and their modes of action have been extensively characterized. The existence of highly conserved mammalian RAD52 epistasis group homologues suggests that information regarding the functions and mechanisms of double strand break repair proteins in yeast may be applicable to mammalian recombinational DNA repair. Two highly conserved human homologues of two RAD52 epistasis group proteins have been identified with demonstrated roles in the repair of DNA double strand breaks and nonhomologous DNA enjoining, hMRE11 and hRAD50. In previous work, the principal investigator has established that these proteins exist in a large, multiprotein complex, referred to herein as the hMrell/hRad50 protein complex. The goal of this proposal is to define the function(s) of the Mrell/Rad50 protein complex in human and murine cells. It is hypothesized that the complex is important for the repair of ionizing radiation-induced DNA damage as well as for DNA recombination in somatic and meiotic cells. Based on the phenotype of the corresponding S. cerevisiae mutants, it is hypothesized that functional impairment of the mammalian Mrell/Rad50 protein complex will lead to ionizing radiation sensitivity, recombinational defects, and genomic instability. Since genomic instability in mammalian cell is invariable linked to malignancy, we further hypothesize that recapitulation of the S. cerevisiae phenotype in mammalian cells will predispose malignancy. In this proposal, the principal investigator will examine the hMrell/hRad50 protein complex from three complementary perspectives; first, at the biochemical level, second, at the cellular level, and finally, in vivo through the creation of a murad50 mutant mouse.