Structural insights into NHEJ: building up an integrated picture of the dynamic DSB repair super complex, one component and interaction at a time.
Structural insights into NHEJ: building up an integrated picture of the dynamic DSB repair super complex, one component and interaction at a time.
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NHEJ的结构洞察力：建立动态DSB修复超级复合物，一个组件和相互作用的集成图片。
DOI：
10.1016/j.dnarep.2014.02.009
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发表时间：
2014-05
期刊：
影响因子：
3.8
通讯作者：
Tainer, John A.
中科院分区：
文献类型：
--
作者：
Williams, Gareth J.;Hammel, Michal;Radhakrishnan, Sarvan Kumar;Ramsden, Dale;Lees-Miller, Susan P.;Tainer, John A.
非同源末端连接（NHEJ）是人类细胞中DNA双链断裂（DSB）修复的主要途径。NHEJ也是脊椎动物免疫系统中V（D）J重组和T和B细胞发育所需的，并且在非同源染色体易位的产生和预防中起作用，非同源染色体易位是基因组不稳定性和许多人类癌症的标志。X射线晶体结构、冷冻电子显微镜包膜和小角X射线散射（SAXS）溶液构象和组装定义了NHEJ的大多数核心蛋白组分：Ku 70/Ku 80异二聚体; DNA依赖性蛋白激酶催化亚基结构特异性内切核酸酶Artemis沿着多核苷酸激酶/磷酸酶（PNKP）、aprataxin和PNKP相关蛋白（APLF）;支架蛋白XRCC 4和XLF（XRCC 4样因子）; DNA聚合酶和DNA连接酶IV（Lig IV）。多蛋白质NHEJ复合物在DSB处的动态组装部分受蛋白质磷酸化调节。NHEJ的基本步骤已被生物化学定义为需要：1）通过Ku异二聚体进行DSB检测，随后DNA-PKcs系留以形成DNA-PKcs-Ku-DNA复合物（称为DNA-PK），2）损伤处理，和3）通过Lig IV进行DNA末端连接，其与XRCC 4和XLF复合起作用。目前，通过组合方法进行的结构整合正在解决关于这三个基本步骤的机制、协调和调节的难题。总的来说，结构结果表明NHEJ系统与DNA-PKcs HEAT重复序列形成弯曲支架，该DNA-PKcs HEAT重复序列充当可压缩的大分子弹簧，适于储存和释放构象能以施加力来调节NHEJ复合物和DNA底物，用于DNA末端保护、加工和连接。
Non-homologous end joining (NHEJ) is the major pathway for repair of DNA double-strand breaks (DSBs) in human cells. NHEJ is also needed for V(D)J recombination and the development of T and B cells in vertebrate immune systems, and acts in both the generation and prevention of non-homologous chromosomal translocations, a hallmark of genomic instability and many human cancers. X-ray crystal structures, cryo-electron microscopy envelopes, and small angle X-ray scattering (SAXS) solution conformations and assemblies are defining most of the core protein components for NHEJ: Ku70/Ku80 heterodimer; the DNA dependent protein kinase catalytic subunit (DNA-PKcs); the structure-specific endonuclease Artemis along with polynucleotide kinase/phosphatase (PNKP), aprataxin and PNKP related protein (APLF); the scaffolding proteins XRCC4 and XLF (XRCC4-like factor); DNA polymerases, and DNA ligase IV (Lig IV). The dynamic assembly of multi-protein NHEJ complexes at DSBs is regulated in part by protein phosphorylation. The basic steps of NHEJ have been biochemically defined to require: 1) DSB detection by the Ku heterodimer with subsequent DNA-PKcs tethering to form the DNA-PKcs-Ku-DNA complex (termed DNA-PK), 2) lesion processing, and 3) DNA end ligation by Lig IV, which functions in complex with XRCC4 and XLF. The current integration of structures by combined methods is resolving puzzles regarding the mechanisms, coordination and regulation of these three basic steps. Overall, structural results suggest the NHEJ system forms a flexing scaffold with the DNA-PKcs HEAT repeats acting as compressible macromolecular springs suitable to store and release conformational energy to apply forces to regulate NHEJ complexes and the DNA substrate for DNA end protection, processing, and ligation.
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