Dynamics of MutS-mismatched DNA complexes are predictive of their repair phenotypes.
Dynamics of MutS-mismatched DNA complexes are predictive of their repair phenotypes.
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MUTS不匹配的DNA复合物的动力学可预测其修复表型。
DOI：
10.1021/bi401429b
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发表时间：
2014-04-01
期刊：
影响因子：
2.9
通讯作者：
Erie, Dorothy A.
中科院分区：
文献类型：
--
作者：
DeRocco, Vanessa C.;Sass, Lauryn E.;Qiu, Ruoyi;Weninger, Keith R.;Erie, Dorothy A.
MutS识别新复制DNA中的碱基错配和碱基插入/缺失（IDL）。MutS和这些错误之间的特定相互作用触发了一系列蛋白质-蛋白质相互作用，最终导致它们的修复。无法解释为什么不同的DNA错误在体内修复的效率差异很大，这仍然是我们对这一过程知识有限的一个突出例子。在这里，我们提出了单分子Förster共振能量转移测量的DNA弯曲动力学引起的栖热菌MutS和E41 A突变体的MutS，这是已知的错误特定缺陷的信号修复。我们比较了三种DNA错配/IDL（T-凸起，GT和CC）的修复效率从高到低。我们确定了三种主要的DNA弯曲状态[轻微弯曲/未弯曲（U），中度弯曲（I），和显着弯曲（B）]，并发现不同的复合物的状态之间的相互转换的动力学变化很大。MutS-错配/IDL复合物的稳定性增加与U的稳定性和B到U的转变势垒的降低相关。铀的不稳定总是伴随着B的不稳定，支持了B是铀“必需的”前体的观点。MutS和MutS-E41 A在GT和T凸起上的动力学比较表明，与MutS的氢键结合促进了碱基-碱基氢键结合的变化，这是实现U状态所需的，这与修复信号传导有关。与修复倾向一起，我们的数据表明，MutS-错配的DNA复合物的弯曲动力学可以控制进入修复的下游信号传导的功能途径。
MutS recognizes base–base mismatches and base insertions/deletions (IDLs) in newly replicated DNA. Specific interactions between MutS and these errors trigger a cascade of protein–protein interactions that ultimately lead to their repair. The inability to explain why different DNA errors are repaired with widely varying efficiencies in vivo remains an outstanding example of our limited knowledge of this process. Here, we present single-molecule Förster resonance energy transfer measurements of the DNA bending dynamics induced by Thermus aquaticus MutS and the E41A mutant of MutS, which is known to have error specific deficiencies in signaling repair. We compared three DNA mismatches/IDLs (T-bulge, GT, and CC) with repair efficiencies ranging from high to low. We identify three dominant DNA bending states [slightly bent/unbent (U), intermediately bent (I), and significantly bent (B)] and find that the kinetics of interconverting among states varies widely for different complexes. The increased stability of MutS–mismatch/IDL complexes is associated with stabilization of U and lowering of the B to U transition barrier. Destabilization of U is always accompanied by a destabilization of B, supporting the suggestion that B is a “required” precursor to U. Comparison of MutS and MutS-E41A dynamics on GT and the T-bulge suggests that hydrogen bonding to MutS facilitates the changes in base–base hydrogen bonding that are required to achieve the U state, which has been implicated in repair signaling. Taken together with repair propensities, our data suggest that the bending kinetics of MutS–mismatched DNA complexes may control the entry into functional pathways for downstream signaling of repair.
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影响因子：
4.8
作者：
Schofield, MJ;Brownewell, FE;Hsieh, P
通讯作者：
Hsieh, P
影响因子：
2.9
作者：
Sass, Lauryn E.;Lanyi, Cherie;Erie, Dorothy A.
通讯作者：
Erie, Dorothy A.
DOI：
10.1073/pnas.0334858100
发表时间：
2003-02-04
影响因子：
11.1
作者：
Loeb, LA;Loeb, KR;Anderson, JP
通讯作者：
Anderson, JP
影响因子：
14.9
作者：
Natrajan, G;Lamers, MH;Sixma, TK
通讯作者：
Sixma, TK
影响因子：
3.8
作者：
Holmes, Shannon F.;Scarpinato, Karin Drotschmann;Kunkel, Thomas A.
通讯作者：
Kunkel, Thomas A.