The Progeroid Phenotype of Ku80 Deficiency Is Dominant over DNA-PK_CS Deficiency

<div><p>Ku80 and DNA-PK_CS are both involved in the repair of double strand DNA breaks via the nonhomologous end joining (NHEJ) pathway. While <i>ku80^−/−</i> mice exhibit a severely reduced lifespan and size, this phenotype is less pronounced in <i>dna-pk_cs^−/−</i> mice. However, these observations are based on independent studies with varying genetic backgrounds. Here, we generated <i>ku80^−/−</i>, <i>dna-pk_cs^−/−</i> and double knock out mice in a C57Bl6/J*FVB F1 hybrid background and compared their lifespan, end of life pathology and mutation frequency in liver and spleen using a lacZ reporter. Our data confirm that inactivation of Ku80 and DNA-PK_CS causes reduced lifespan and bodyweights, which is most severe in <i>ku80^−/−</i> mice. All mutant mice exhibited a strong increase in lymphoma incidence as well as other aging-related pathology (skin epidermal and adnexal atrophy, trabacular bone reduction, kidney tubular anisokaryosis, and cortical and medullar atrophy) and severe lymphoid depletion. LacZ mutation frequency analysis did not show strong differences in mutation frequencies between knock out and wild type mice. The <i>ku80^−/−</i> mice had the most severe phenotype and the Ku80-mutation was dominant over the DNA-PK_CS-mutation. Presumably, the more severe degenerative effect of Ku80 inactivation on lifespan compared to DNA-PK_CS inactivation is caused by additional functions of Ku80 or activity of free Ku70 since both Ku80 and DNA-PK_CS are essential for NHEJ.</p>