Ku70 functions in addition to nonhomologous end joining in pancreatic beta-cells: A connection to beta-catenin regulation

191 words, Main text: 3994 words, 5 figures (three color), 4 online sup. 50 references Running Title: Increased β -cell proliferation in Ku70 -/mice Page 1 of 41 Diabetes Diabetes Publish Ahead of Print, published online March 8, 2013 2 Abstract The genesis of β-cells predominantly occurs through self-replication, therefore, understanding the regulation of cell proliferation is essential. We previously showed that the lack of nonhomologous end joining (NHEJ) DNA repair factor Ligase IV led to an accumulation of DNA damage, which permanently halted β-cell proliferation and dramatically decreased insulin production, causing overt diabetes in a hypomorphic p53 R172P background. In this report, to further delineate the function of NHEJ, we analyzed mice deficient for another key NHEJ factor, Ku70, to discover the effect of cellular responses to DNA damage in pancreatic β-cells on cellular proliferation and glucose homeostasis. Analysis of Ku70 -/pancreatic β-cells revealed an accumulation of DNA damage and activation of p53-dependent cellular senescence, similar to the results found in our Ligase IV deficiency study. To our surprise, Ku70 -/mice had significantly increased β-cell proliferation and islet expansion, heightened insulin levels and decreased glycemia. This augmented β-cell proliferation was accompanied by an increased βcatenin level, which we propose to be responsible for this phenotype. Our study highlights Ku70 as an important player in not only maintaining genomic stability through NHEJ-dependent functions but also regulating pancreatic β-cell proliferation, a novel NHEJ-independent function.