Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001, Haryana, India.
Manipal University, Manipal, 576104, Karnataka, India.
Nucleic Acids Res. 2018 Jan 9;46(1):256-266. doi: 10.1093/nar/gkx1149.
The DNA mismatch repair (MMR) pathway removes errors that appear during genome replication. MutS is the primary mismatch sensor and forms an asymmetric dimer that encircles DNA to bend it to scan for mismatches. The mechanism utilized to load DNA into the central tunnel was unknown and the origin of the force required to bend DNA was unclear. We show that, in absence of DNA, MutS forms a symmetric dimer wherein a gap exists between the monomers through which DNA can enter the central tunnel. The comparison with structures of MutS-DNA complexes suggests that the mismatch scanning monomer (Bm) will move by nearly 50 Å to associate with the other monomer (Am). Consequently, the N-terminal domains of both monomers will press onto DNA to bend it. The proposed mechanism of toroid formation evinces that the force required to bend DNA arises primarily due to the movement of Bm and hence, the MutS dimer acts like a pair of pliers to bend DNA. We also shed light on the allosteric mechanism that influences the expulsion of adenosine triphosphate from Am on DNA binding. Overall, this study provides mechanistic insight regarding the primary event in MMR i.e. the assembly of the MutS-DNA complex.
DNA 错配修复（MMR）途径可消除基因组复制过程中出现的错误。MutS 是主要的错配传感器，它形成不对称二聚体，环绕 DNA 弯曲以扫描错配。将 DNA 加载到中央隧道的机制尚不清楚，弯曲 DNA 所需的力的来源也不清楚。我们表明，在没有 DNA 的情况下，MutS 形成对称二聚体，其中单体之间存在一个间隙，DNA 可以通过该间隙进入中央隧道。与 MutS-DNA 复合物的结构比较表明，错配扫描单体（Bm）将移动近 50 Å 与另一个单体（Am）结合。因此，两个单体的 N 端结构域将压在 DNA 上使其弯曲。拟议的环形成机制表明，弯曲 DNA 所需的力主要源于 Bm 的运动，因此 MutS 二聚体的作用就像一对钳子一样使 DNA 弯曲。我们还揭示了影响 DNA 结合时 Am 中三磷酸腺苷（ATP）排出的变构机制。总体而言，这项研究为 MMR 的主要事件（即 MutS-DNA 复合物的组装）提供了机制上的见解。
