Cryo-EM of NHEJ supercomplexes provides insights into DNA repair.
Cryo-EM of NHEJ supercomplexes provides insights into DNA repair.
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DOI：
10.1016/j.molcel.2021.07.005
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发表时间：
2021-08-19
期刊：
影响因子：
16
通讯作者：
Blundell, Tom L.
中科院分区：
文献类型：
--
作者：
Chaplin, Amanda K.;Hardwick, Steven W.;Stavridi, Antonia Kefala;Buehl, Christopher J.;Goff, Noah J.;Ropars, Virginie;Liang, Shikang;De Oliveira, Taiana Maia;Chirgadze, Dimitri Y.;Meek, Katheryn;Charbonnier, Jean-Baptiste;Blundell, Tom L.
非同源末端连接(NHEJ)是人类修复DNA双链断裂(DSB)的两种重要机制之一。未修复或修复不当的DSB可能会导致细胞凋亡或癌症。NHEJ涉及多种蛋白质，包括Ku70/80异二聚体、DNA依赖的蛋白激酶催化亚基(DNA-PKcs)、X射线交叉互补蛋白4(XRCC4)、XRCC4样因子(XLF)和连接酶IV。这些核心蛋白结合DSB并连接受损的DNA末端。然而，这些蛋白质的结构组装细节仍不清楚。在这里，我们展示了由这些核心蛋白和DNA组成的NHEJ超复合体的冷冻EM结构，揭示了该组装的详细结构。我们描述了这种超复合体的单体和二聚体形式，并提出了长程突触复合体的交替二聚体形式的存在。最后，我们表明，这些NHEJ复合体中几个结构特征的突变破坏对DNA修复具有负面影响。非同源末端连接(NHEJ)是修复DNA双链断裂的关键机制。使用冷冻-EM，卓别林等人。展示了核心NHEJ蛋白的单体和二聚体结构，并揭示了它们的结构架构。两个长距离突触二聚体被提出，二聚体界面的突变对DNA修复产生负面影响。
Non-homologous end joining (NHEJ) is one of two critical mechanisms utilized in humans to repair DNA double-strand breaks (DSBs). Unrepaired or incorrect repair of DSBs can lead to apoptosis or cancer. NHEJ involves several proteins, including the Ku70/80 heterodimer, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), X-ray cross-complementing protein 4 (XRCC4), XRCC4-like factor (XLF), and ligase IV. These core proteins bind DSBs and ligate the damaged DNA ends. However, details of the structural assembly of these proteins remain unclear. Here, we present cryo-EM structures of NHEJ supercomplexes that are composed of these core proteins and DNA, revealing the detailed structural architecture of this assembly. We describe monomeric and dimeric forms of this supercomplex and also propose the existence of alternate dimeric forms of long-range synaptic complexes. Finally, we show that mutational disruption of several structural features within these NHEJ complexes negatively affects DNA repair. Non-homologous end joining (NHEJ) is a key mechanism that repairs DNA-double strand breaks. Using cryo-EM, Chaplin et al. present monomeric and dimeric structures of the core NHEJ proteins and reveal their structural architecture. Two long-range synaptic dimers are presented, and mutations of the dimer interfaces negatively affect DNA repair.
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DOI：
10.1016/s0921-8777(98)00063-9
发表时间：
1999-01-26
期刊：
MUTATION RESEARCH-DNA REPAIR
影响因子：
--
作者：
Bryans, M;Valenzano, MC;Stamato, TD
通讯作者：
Stamato, TD
DOI：
10.4049/jimmunol.1501654
发表时间：
2016-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Neal JA;Xu Y;Abe M;Hendrickson E;Meek K
通讯作者：
Meek K
XLF在非同源末端连接期间充当灵活的连接器。
影响因子：
7.7
作者：
Carney SM;Moreno AT;Piatt SC;Cisneros-Aguirre M;Lopezcolorado FW;Stark JM;Loparo JJ
通讯作者：
Loparo JJ
影响因子：
14.9
作者：
Jovanovic, M;Dynan, WS
通讯作者：
Dynan, WS
DOI：
10.1016/j.str.2020.12.006
发表时间：
2021-05-06
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Hepburn M;Saltzberg DJ;Lee L;Fang S;Atkinson C;Strynadka NCJ;Sali A;Lees-Miller SP;Schriemer DC
通讯作者：
Schriemer DC