Warren Joshua J, Pohlhaus Timothy J, Changela Anita, Iyer Ravi R, Modrich Paul L, Beese Lorena S
Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
Mol Cell. 2007 May 25;26(4):579-92. doi: 10.1016/j.molcel.2007.04.018.
Mismatch repair (MMR) ensures the fidelity of DNA replication, initiates the cellular response to certain classes of DNA damage, and has been implicated in the generation of immune diversity. Each of these functions depends on MutSalpha (MSH2*MSH6 heterodimer). Inactivation of this protein complex is responsible for tumor development in about half of known hereditary nonpolyposis colorectal cancer kindreds and also occurs in sporadic tumors in a variety of tissues. Here, we describe a series of crystal structures of human MutSalpha bound to different DNA substrates, each known to elicit one of the diverse biological responses of the MMR pathway. All lesions are recognized in a similar manner, indicating that diversity of MutSalpha-dependent responses to DNA lesions is generated in events downstream of this lesion recognition step. This study also allows rigorous mapping of cancer-causing mutations and furthermore suggests structural pathways for allosteric communication between different regions within the heterodimer.
错配修复（MMR）确保DNA复制的保真度，引发细胞对某些类型DNA损伤的反应，并与免疫多样性的产生有关。这些功能中的每一个都依赖于MutSα（MSH2*MSH6异二聚体）。这种蛋白质复合物的失活在大约一半已知的遗传性非息肉病性结直肠癌家族中导致肿瘤发生，并且也发生在各种组织的散发性肿瘤中。在这里，我们描述了与不同DNA底物结合的人MutSα的一系列晶体结构，每种底物已知会引发MMR途径的多种生物学反应之一。所有损伤都以类似的方式被识别，这表明在该损伤识别步骤下游的事件中产生了MutSα对DNA损伤的依赖性反应的多样性。这项研究还允许对致癌突变进行精确映射，并且进一步提出了异二聚体内不同区域之间变构通讯的结构途径。
