| First Author | Tavana O | Year | 2013 |
| Journal | Diabetes | Volume | 62 |
| Issue | 7 | Pages | 2429-38 |
| PubMed ID | 23474484 | Mgi Jnum | J:208670 |
| Mgi Id | MGI:5563897 | Doi | 10.2337/db12-1218 |
| Citation | Tavana O, et al. (2013) Ku70 functions in addition to nonhomologous end joining in pancreatic beta-cells: a connection to beta-catenin regulation. Diabetes 62(7):2429-38 |
| abstractText | The genesis of beta-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 leads to an accumulation of DNA damage that permanently halts beta-cell proliferation and dramatically decreases insulin production, causing overt diabetes in a hypomorphic p53(R172P) background. In the present study, 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 beta-cells on cellular proliferation and glucose homeostasis. Analysis of Ku70(-/-) pancreatic beta-cells revealed an accumulation of DNA damage and activation of p53-dependent cellular senescence similar to the results found in our earlier ligase IV deficiency study. To our surprise, Ku70(-/-) mice had significantly increased beta-cell proliferation and islet expansion, heightened insulin levels, and decreased glycemia. This augmented beta-cell proliferation was accompanied by an increased beta-catenin level, which we propose to be responsible for this phenotype. This study highlights Ku70 as an important player not only in maintaining genomic stability through NHEJ-dependent functions, but also in regulating pancreatic beta-cell proliferation, a novel NHEJ-independent function. |
