TY - JOUR
T1 - Ku70 functions in addition to nonhomologous end joining in pancreatic β-Cells
AU - Tavana, Omid
AU - Puebla-Osorio, Nahum
AU - Kim, Jiseong
AU - Sang, Mei
AU - Jang, Stella
AU - Zhu, Chengming
PY - 2013/7
Y1 - 2013/7
N2 - 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 p53R172P 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, Ku702/2 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 b-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.
AB - 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 p53R172P 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, Ku702/2 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 b-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.
UR - http://www.scopus.com/inward/record.url?scp=84883678240&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883678240&partnerID=8YFLogxK
U2 - 10.2337/db12-1218
DO - 10.2337/db12-1218
M3 - Article
C2 - 23474484
AN - SCOPUS:84883678240
SN - 0012-1797
VL - 62
SP - 2429
EP - 2438
JO - Diabetes
JF - Diabetes
IS - 7
ER -