title: Ku70 functions in addition to nonhomologous end joining in pancreatic β-cells: a connection to β-catenin regulation.
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 leads to an accumulation of DNA damage that permanently halts β-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 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 earlier 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 β-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 β-cell proliferation, a novel NHEJ-independent function.
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Tavana
authors.forename: Nahum
authors.initials: N
authors.lastname: Puebla-Osorio
authors.forename: Jiseong
authors.initials: J
authors.lastname: Kim
authors.forename: Mei
authors.initials: M
authors.lastname: Sang
authors.forename: Stella
authors.initials: S
authors.lastname: Jang
authors.forename: Chengming
authors.initials: C
authors.lastname: Zhu
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics; D004249:DNA Damage; D059766:DNA End-Joining Repair / Q000502:physiology; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D000072200:Ku Autoantigen; D051379:Mice; D008822:Mice, Transgenic; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D034961:Antigens, Nuclear; D001786:Blood Glucose; D004268:DNA-Binding Proteins; D007328:Insulin; D051176:beta Catenin; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen; D011088:DNA Ligases; D000072481:DNA Ligase ATP