DNA Ligase IV Guides End-Processing Choice during Nonhomologous End Joining.
DNA Ligase IV Guides End-Processing Choice during Nonhomologous End Joining.
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DOI：
10.1016/j.celrep.2017.08.091
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发表时间：
2017-09-19
期刊：
影响因子：
8.8
通讯作者：
Rothenberg E
中科院分区：
文献类型：
--
作者：
Conlin MP;Reid DA;Small GW;Chang HH;Watanabe G;Lieber MR;Ramsden DA;Rothenberg E
非同源末端连接(NHEJ)在染色体断裂修复过程中必须适应不同的末端结构。在这里，我们研究这种灵活性的机械基础。DNA末端由Ku、XLF、XRCC4和DNA连接酶IV(LIG4)在配对末端复合体(PEC)中对齐；我们通过单分子分析展示了末端错配如何导致PEC内末端的动员，并随后采样更多的末端对齐配置。在细胞NHEJ过程中，这种重塑对于直接连接受损和错配的末端是必不可少的，因为这些末端的重塑和结扎都需要一个LIG4特异的结构基序，即插入1。插入1也是PEC重塑所必需的，当末端结构阻止直接连接时，PEC重塑能够进行核溶解处理。因此，表达缺乏插入1的LIG4的细胞对电离辐射敏感。因此，不同末端的细胞NHEJ通过LIG4介导的末端结构差异感知以及随后对齐末端的动态重塑来识别修复所需的步骤。Conlin等人。研究表明，当DNA双链断裂有末端错配或损伤时，DNA连接酶4特有的非结构化环允许动态重塑比对和末端修复；该环也是细胞抵抗电离辐射所必需的。
Nonhomologous end joining (NHEJ) must adapt to diverse end structures during repair of chromosome breaks. Here we investigate the mechanistic basis for this flexibility. DNA ends are aligned in a paired-end complex (PEC) by Ku, XLF, XRCC4, and DNA ligase IV (LIG4); we show by single-molecule analysis how terminal mispairs lead to mobilization of ends within PECs, and consequent sampling of more end-alignment configurations. This remodeling is essential for direct ligation of damaged and mispaired ends during cellular NHEJ, since remodeling and ligation of such ends both require a LIG4-specific structural motif, insert1. Insert1 is also required for PEC remodeling that enables nucleolytic processing when end structures block direct ligation. Accordingly, cells expressing LIG4 lacking insert1 are sensitive to ionizing radiation. Cellular NHEJ of diverse ends thus identifies the steps necessary for repair through LIG4-mediated sensing of differences in end structure, and consequent dynamic remodeling of aligned ends. Conlin et al. show that when DNA double-strand breaks have terminal mispairs or damage, an unstructured loop unique to DNA ligase 4 allows for dynamic remodeling of the alignment and end-repair; the loop is also required for cellular resistance to ionizing radiation.
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DOI：
10.1038/nrc2607
发表时间：
2009-05
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1126/science.1261971
发表时间：
2015-01-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ochi T;Blackford AN;Coates J;Jhujh S;Mehmood S;Tamura N;Travers J;Wu Q;Draviam VM;Robinson CV;Blundell TL;Jackson SP
通讯作者：
Jackson SP
影响因子：
3.8
作者：
Greco, George E.;Matsumoto, Yoshihiro;Brooks, Rhys C.;Lu, Zhengfei;Lieber, Michael R.;Tomkinson, Alan E.
通讯作者：
Tomkinson, Alan E.
影响因子：
4.5
作者：
Gómez-Herreros F;Romero-Granados R;Zeng Z;Alvarez-Quilón A;Quintero C;Ju L;Umans L;Vermeire L;Huylebroeck D;Caldecott KW;Cortés-Ledesma F
通讯作者：
Cortés-Ledesma F
影响因子：
64.8
作者：
Pascal, JM;O'Brien, PJ;Ellenberger, T
通讯作者：
Ellenberger, T