Roles of Mre11 in lymphocyte development and DNA repair

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DESCRIPTION (provided by applicant): Humans that inherit mutations in the Mre11 gene suffer from extreme sensitivity to ionizing radiation, develop cerebellar degeneration, and have frequent chromosomal translocations in circulating lymphocytes. In addition, somatic mutation of Mre11 has been found in association with various tumors. The Mre11 protein is a member of a complex involved in DNA repair and in the overall cellular responses to DNA damage. 3 proteins comprise this complex; Mre11, Rad50 and NBS. Homologues of Mre11 and Rad50 are conserved from bacteria to metazoans. NBS (XRS2 in yeast) is less well conserved at the amino acid level, but is still required. In vitro biochemical studies and in vivo analyses in yeast have demonstrated that Mre11 possesses single strand DNA endonuclease, single strand DNA exonuclease, and double strand DNA binding activities. The protein is modular in that all nuclease activities are confined to the N terminal region while double strand DNA binding is confined to the C terminus. Much remains to be learned about Mre11 in mammals because studies have been hampered by the cellular lethality of null alleles in common experimental systems, and the realization that ATLD patients harbor mutant alleles that maintain significant protein function. This problem is especially highlighted by the lack of any existing mammalian mutation that inactivates the endo-and exonuclease activities of Mre11 arguably 1 of the most important functions of the Mre11, Rad50, NBS complex. Herein is described the completed construction of the first mouse deficient for the nuclease activities of Mre11. Experiments are proposed which will answer many questions regarding the roles of the highly conserved Mre11 nuclease during normal cell growth, in response to DNA damage, and in specialized recombination events in lymphocytes and gametocytes. These studies may contribute significantly to our understanding of the multifunctional Mre11 protein and its roles in human health and disease.