Ku70 Functions in Addition to Nonhomologous End Joining in Pancreatic b-Cells A Connection to b-Catenin Regulation
Ku70 Functions in Addition to Nonhomologous End Joining in Pancreatic b-Cells A Connection to b-Catenin Regulation
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
O. Tavana;N. Puebla-Osorio;Jiseong Kim;M. Sang;S. Jang;Chengming Zhu
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作者：
O. Tavana;N. Puebla-Osorio;Jiseong Kim;M. Sang;S. Jang;Chengming Zhu
B细胞的发生主要是通过自我复制；因此，了解细胞增殖的调节是至关重要的。我们之前已经证明，缺乏非同源末端连接(NHEJ)DNA修复因子连接酶IV会导致DNA损伤的积累，从而永久性地阻止b细胞的增殖，并显著减少胰岛素的产生，在P53基因亚型背景下导致明显的糖尿病。在本研究中，为了进一步阐明NHEJ的功能，我们分析了另一个关键的NHEJ因子Ku70缺失的小鼠，以发现胰腺b细胞对DNA损伤的细胞反应对细胞增殖和葡萄糖稳态的影响。对Ku70胰腺b细胞的分析显示，DNA损伤的积累和依赖于P53的细胞衰老的激活与我们早期的连接酶IV缺陷研究中发现的结果相似。令我们惊讶的是，Ku70小鼠显著促进了b细胞的增殖和胰岛的扩张，提高了胰岛素水平，并降低了血糖。这种增强的b细胞增殖伴随着b-连环蛋白水平的升高，我们认为这与这种表型有关。这项研究强调Ku70不仅在通过NHEJ依赖功能维持基因组稳定性方面发挥重要作用，而且在调节胰腺b细胞增殖方面也发挥着重要作用，这是一种新的NHEJ非依赖功能。糖尿病62：2429-2438,2013
The genesis of b-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 b-cell proliferation and dramatically decreases insulin production, causing overt diabetes in a hypomorphic p53 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 b-cells on cellular proliferation and glucose homeostasis. Analysis of Ku70 pancreatic b-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 b-cell proliferation and islet expansion, heightened insulin levels, and decreased glycemia. This augmented b-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 b-cell proliferation, a novel NHEJ-independent function. Diabetes 62:2429–2438, 2013