Envisioning the dynamics and flexibility of Mre11-Rad50-Nbs1 complex to decipher its roles in DNA replication and repair.
Envisioning the dynamics and flexibility of Mre11-Rad50-Nbs1 complex to decipher its roles in DNA replication and repair.
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DOI：
10.1016/j.pbiomolbio.2014.12.004
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发表时间：
2015-03
影响因子：
3.8
通讯作者：
Tainer JA
中科院分区：
文献类型：
--
作者：
Lafrance-Vanasse J;Williams GJ;Tainer JA
Mre 11-Rad 50-Nbs 1（MRN）复合物是一种动态大分子机器，作用于DNA双链断裂修复的第一步，其每个组分都具有与其功能直接相关的内在动力学和柔性特性。因此，破译MRN复合物的功能结构生物学正在推动新的集成技术来定义与DNA相互作用的蛋白质机制的动态结构生物学。Rad 50通过其卷曲螺旋和锌钩结构域促进显著的长程变构。它的ATP酶活性驱动单体和二聚体形式之间的动态转变，这可以用改变ATP酶速率的突变体来调节，以控制末端连接与切除活性。Mre 11的双重内切和外切核酸酶活性在修复途径选择中的生物学功能一直是谜，直到最近，当它们被特定核酸酶抑制剂的发展所揭示。Mre 11二聚体的灵活性，这可能是在细胞中调节，以控制MRN功能，表明新的抑制剂设计策略的癌症干预。Nbs 1具有FHA和BRCT结构域，以结合进一步调节MRN的多个相互作用伴侣。其中之一，CtIP，调节同源重组修复的Mre 11切除活性。总的来说，这些组合特性表明了新的治疗策略。此外，它们共同有助于解释MRN如何调节DNA修复途径的选择，这对改善采用DNA损伤剂或靶向DNA损伤反应的癌症临床试验的设计和分析具有重要意义。
The Mre11-Rad50-Nbs1 (MRN) complex is a dynamic macromolecular machine that acts in the first steps of DNA double strand break repair, and each of its components has intrinsic dynamics and flexibility properties that are directly linked with their functions. As a result, deciphering the functional structural biology of the MRN complex is driving novel and integrated technologies to define the dynamic structural biology of protein machinery interacting with DNA. Rad50 promotes dramatic long-range allostery through its coiled-coil and zinc-hook domains. Its ATPase activity drives dynamic transitions between monomeric and dimeric forms that can be modulated with mutants modifying the ATPase rate to control end joining versus resection activities. The biological functions of Mre11’s dual endo- and exonuclease activities in repair pathway choice were enigmatic until recently, when they were unveiled by the development of specific nuclease inhibitors. Mre11 dimer flexibility, which may be regulated in cells to control MRN function, suggests new inhibitor design strategies for cancer intervention. Nbs1 has FHA and BRCT domains to bind multiple interaction partners that further regulate MRN. One of them, CtIP, modulates the Mre11 excision activity for homologous recombination repair. Overall, these combined properties suggest novel therapeutic strategies. Furthermore, they collectively help to explain how MRN regulates DNA repair pathway choice with implications for improving the design and analysis of cancer clinical trials that employ DNA damaging agents or target the DNA damage response.
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影响因子：
64.5
作者：
Duda, David M.;Borg, Laura A.;Scott, Daniel C.;Hunt, Harold W.;Hammel, Michal;Schulman, Brenda A.
通讯作者：
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DOI：
10.1126/science.1164424
发表时间：
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期刊：
Science (New York, N.Y.)
影响因子：
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DOI：
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发表时间：
2013-11-19
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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