Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities.
Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities.
复制标题
DOI：
10.1016/j.mrfmmm.2012.12.008
复制
发表时间：
2013-03
影响因子：
2.3
通讯作者：
Williams, Kandace J.
中科院分区：
文献类型：
--
作者：
Edelbrock, Michael A.;Kaliyaperumal, Saravanan;Williams, Kandace J.
自从发现细菌中的MutHLS修复系统后，DNA错配修复(MMR)的领域迅速扩大。到20世纪90年代中期，酵母和人类对细菌MutL和MutS的同源物已经被鉴定出来，它们在遗传性非息肉病性结直肠癌(HNPCC；Lynch综合征)中的作用正在深入研究中。人MutS同源6蛋白(HMSH6)于1995年首次报道，它是hMSH2的G：T结合伙伴，形成hMutSα错配结合复合体。每个hMutSα复合体的信号转导是由hMutLα异源二聚体(hMLH1和hPMS2)完成的。单个MMR蛋白的分子机制和细胞调控现在是深入研究的领域。这篇综述将集中于与错配结合相关的分子机制，以及新出现的证据表明，mutsmsms6，特别是α，是依赖mmr的DNA损伤反应和与细胞内其他DNA修复途径沟通的关键蛋白。MSH6在没有MSH2的情况下是不稳定的，但它是这个异源二聚体的DNA损伤结合伙伴。MSH6，但不是MSH2，具有一个保守的Phe-X-Glu基序，可以识别并结合几种不同的DNA结构扭曲，启动不同的细胞反应。HMSH6还包含将hMutSα穿梭到核中所需的核定位序列。例如，一旦与O6meG：T结合，MSH6就会触发DNA损伤反应，涉及这种独特蛋白质的N端无序区域内的磷酸化改变。虽然许多研究都集中在MMR作为一种复制后DNA修复机制，但MMR蛋白在细胞周期的所有阶段都有表达和活性。关于需要mutsα，特别是msh6存在的调控细胞角色，还有更多的有待发现。
The field of DNA mismatch repair (MMR) has rapidly expanded after the discovery of the MutHLS repair system in bacteria. By the mid 1990s yeast and human homologues to bacterial MutL and MutS had been identified and their contribution to hereditary non-polyposis colorectal cancer (HNPCC; Lynch Syndrome) was under intense investigation. The human MutS homologue 6 protein (hMSH6), was first reported in 1995 as a G:T binding partner (GTBP) of hMSH2, forming the hMutSα mismatch-binding complex. Signal transduction from each DNA-bound hMutSα complex is accomplished by the hMutLα heterodimer (hMLH1 and hPMS2). Molecular mechanisms and cellular regulation of individual MMR proteins are now areas of intensive research. This review will focus on molecular mechanisms associated with mismatch binding, as well as emerging evidence that MutSα and in particular, MSH6, is a key protein in MMR-dependent DNA damage response and communication with other DNA repair pathways within the cell. MSH6 is unstable in the absence of MSH2, however it is the DNA lesion-binding partner of this heterodimer. MSH6, but not MSH2, has a conserved Phe-X-Glu motif that recognizes and binds several different DNA structural distortions, initiating different cellular responses. hMSH6 also contains the nuclear localization sequences required to shuttle hMutSα into the nucleus. For example, upon binding to O6meG:T, MSH6 triggers a DNA damage response that involves altered phosphorylation within the N-terminal disordered domain of this unique protein. While many investigations have focused on MMR as a post-replication DNA repair mechanism, MMR proteins are expressed and active in all phases of the cell cycle. There is much more to be discovered about regulatory cellular roles that require the presence of MutSα and, in particular, MSH6.
登录
查看更多内容
影响因子：
30.8
作者：
Brown, KD;Rathi, A;Baskaran, R
通讯作者：
Baskaran, R
影响因子：
3.5
作者：
Bjelland, S;Seeberg, E
通讯作者：
Seeberg, E
影响因子：
4.8
作者：
Cannavo, Elda;Gerrits, Bertran;Jiricny, Josef
通讯作者：
Jiricny, Josef
影响因子：
--
作者：
Edelbrock M;He H;Schroering A;Fernstrom M;Bathala S;Williams KJ
通讯作者：
Williams KJ
影响因子：
7.8
作者：
Chahwan R;Edelmann W;Scharff MD;Roa S
通讯作者：
Roa S