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Mol. Cell. Biol. doi:10.1128/MCB.00785-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Deletion of Either Ku70, Ku80 or Both Causes Early Aging Without Substantially Increased Cancer

Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center, San Antonio, Texas 78245.; Department of Pathology, Stanford University Medical Center, R241, 300 Pasteur Drive, Palo Alto, CA 94305.; Departments of Radiation Oncology and Immunology, University of Washington, 1959 N.E. Pacific Street, Seattle, WA 98195-6069

^* To whom correspondence should be addressed. Email: hastye{at}uthscsa.edu.

	Abstract

Ku70 forms a heterodimer with Ku80, called Ku that is critical for repairing DNA double-stand breaks by nonhomologous end joining (NHEJ) and for maintaining telomeres. Mice mutated for either gene exhibit a similar phenotype that includes increased sensitivity to ionizing radiation and severe combined immunodeficiency. However, there are also differences in their reported phenotypes. For example, only Ku70-mutants are reported to exhibit a high incidence of thymic lymphomas while only Ku80-mutants are reported to exhibit early aging with very low cancer levels. There are two explanations for these differences. First, either Ku70 or Ku80 function outside the Ku heterodimer such that deletion of one is not identical to deletion of the other. Second, divergent genetic backgrounds/environments influence phenotype. To distinguish between these possibilities, the Ku70 and Ku80 mutations were crossed together to generate Ku70-, Ku80- and double-mutant mice in the same genetic background raised in the same environment. We show these three cohorts have similar phenotypes that most resemble the previous report for Ku80-mutant mice: early aging without substantially increased cancer levels. Thus, our observations suggest that the Ku heterodimer is important for longevity assurance in mice since divergent genetic backgrounds and/or environments likely account for these previously reported differences.

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