MutSβ promotes trinucleotide repeat expansion by recruiting DNA polymerase β to nascent (CAG)n or (CTG)n hairpins for error-prone DNA synthesis.
MutSβ promotes trinucleotide repeat expansion by recruiting DNA polymerase β to nascent (CAG)n or (CTG)n hairpins for error-prone DNA synthesis.
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（CAG）·（CTG）重复序列的扩增导致许多家族性神经退行性疾病。尽管其潜在的机制在很大程度上仍然未知，但参与DNA错配修复的组分，特别是错配识别蛋白MutSβ（MSH 2-MSH 3异源二聚体），涉及（CAG）·（CTG）重复扩增。除了识别小的插入-缺失环外，MutSβ还特异性结合（CAG）n·（CTG）n序列内形成的DNA发夹不完全异源双链体。然而，MutSβ结合是否以及如何触发（CAG）·（CTG）重复序列的扩增仍然未知。我们在这里表明，纯化的重组MutSβ与DNA聚合酶β（Polβ）物理相互作用，并刺激Polβ催化的（CAG）n或（CTG）n发夹保留。与这些体外观察结果一致，MutSβ和Polβ在体内相互作用，并在DNA复制期间共定位于（CAG）·（CTG）重复。我们的数据支持在DNA复制和/或修复过程中MutSβ和Polβ对（CAG）n或（CTG）n发夹的易错加工模型：MutSβ识别新生DNA链中形成的（CAG）n或（CTG）n发夹，并将Polβ招募到复合物中，然后利用发夹作为引物进行延伸，导致（CAG）·（CTG）重复扩增。这项研究提供了一种新的机制，三核苷酸重复扩增在分裂和非分裂细胞。
Expansion of (CAG)•(CTG) repeats causes a number of familial neurodegenerative disorders. Although the underlying mechanism remains largely unknown, components involved in DNA mismatch repair, particularly mismatch recognition protein MutSβ (a MSH2-MSH3 heterodimer), are implicated in (CAG)•(CTG) repeat expansion. In addition to recognizing small insertion-deletion loop-outs, MutSβ also specifically binds DNA hairpin imperfect heteroduplexes formed within (CAG)n•(CTG)n sequences. However, whether or not and how MutSβ binding triggers expansion of (CAG)•(CTG) repeats remain unknown. We show here that purified recombinant MutSβ physically interacts with DNA polymerase β (Polβ) and stimulates Polβ-catalyzed (CAG)n or (CTG)n hairpin retention. Consistent with these in vitro observations, MutSβ and Polβ interact with each other in vivo, and colocalize at (CAG)•(CTG) repeats during DNA replication. Our data support a model for error-prone processing of (CAG)n or (CTG)n hairpins by MutSβ and Polβ during DNA replication and/or repair: MutSβ recognizes (CAG)n or (CTG)n hairpins formed in the nascent DNA strand, and recruits Polβ to the complex, which then utilizes the hairpin as a primer for extension, leading to (CAG)•(CTG) repeat expansion. This study provides a novel mechanism for trinucleotide repeat expansion in both dividing and non-dividing cells.
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影响因子：
64.8
作者：
Kovtun, Irina V.;Liu, Yuan;McMurray, Cynthia T.
通讯作者：
McMurray, Cynthia T.
影响因子：
14.9
作者：
Gannon AM;Frizzell A;Healy E;Lahue RS
通讯作者：
Lahue RS
影响因子：
56.9
作者：
DRUMMOND, JT;LI, GM;MODRICH, P
通讯作者：
MODRICH, P
影响因子：
4.8
作者：
Gradia, S;Acharya, S;Fishel, R
通讯作者：
Fishel, R
DOI：
10.1073/pnas.1105461108
发表时间：
2011-10-18
影响因子：
11.1
作者：
Lang, Walter H.;Coats, Julie E.;McMurray, Cynthia T.
通讯作者：
McMurray, Cynthia T.