Inhibition of Homologous Recombination by DNA-Dependent Protein Kinase Requires Kinase Activity, Is Titratable, and Is Modulated by Autophosphorylation
Inhibition of Homologous Recombination by DNA-Dependent Protein Kinase Requires Kinase Activity, Is Titratable, and Is Modulated by Autophosphorylation
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DOI：
10.1128/mcb.01298-10
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发表时间：
2011-04-01
影响因子：
5.3
通讯作者：
Meek, Katheryn
中科院分区：
文献类型：
--
作者：
Neal, Jessica A.;Dang, Van;Meek, Katheryn
细胞如何在非同源末端连接（NHEJ）和同源重组（HR）之间进行选择以修复双链断裂（DSB）是一个核心且基本上未回答的问题。虽然有证据表明HR和NHEJ之间存在竞争，但由于DNA依赖性蛋白激酶（DNA-PK）的细胞丰度，似乎修复途径的选择必须比直接竞争更多。突变的方法和化学抑制被用来解决DNA-PK如何影响HR. We发现，DNA-PK的抑制HR的能力是滴定和完全依赖于其酶活性。尽管如此，虽然必要的，强大的酶活性是不足以抑制HR。新兴的数据（包括这里提出的数据）文件的DNA-PK的广泛的磷酸化，可能发生在40多个网站的功能复杂性。更重要的是，我们在这里表明，DNA-PK大催化亚基（DNA-PKcs）的某些磷酸化明显促进HR，同时抑制NHEJ，我们得出结论，DNA-PK的磷酸化状态影响细胞如何选择修复DSB。
How a cell chooses between nonhomologous end joining (NHEJ) and homologous recombination (HR) to repair a double-strand break (DSB) is a central and largely unanswered question. Although there is evidence of competition between HR and NHEJ, because of the DNA-dependent protein kinase (DNA-PK)'s cellular abundance, it seems that there must be more to the repair pathway choice than direct competition. Both a mutational approach and chemical inhibition were utilized to address how DNA-PK affects HR. We find that DNA-PK's ability to repress HR is both titratable and entirely dependent on its enzymatic activity. Still, although requisite, robust enzymatic activity is not sufficient to inhibit HR. Emerging data (including the data presented here) document the functional complexities of DNA-PK's extensive phosphorylations that likely occur on more than 40 sites. Even more, we show here that certain phosphorylations of the DNA-PK large catalytic subunit (DNA-PKcs) clearly promote HR while inhibiting NHEJ, and we conclude that the phosphorylation status of DNA-PK impacts how a cell chooses to repair a DSB.