Msh2-Msh3 Interferes with Okazaki Fragment Processing to Promote Trinucleotide Repeat Expansions
Msh2-Msh3 Interferes with Okazaki Fragment Processing to Promote Trinucleotide Repeat Expansions
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DOI：
10.1016/j.celrep.2012.06.020
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发表时间：
2012-08-01
期刊：
影响因子：
8.8
通讯作者：
Bambara, Robert A.
中科院分区：
文献类型：
--
作者：
Kantartzis, Athena;Williams, Gregory M.;Bambara, Robert A.
三核苷酸重复序列（TNR）扩增是40多种神经退行性和神经肌肉疾病的潜在原因，包括肌强直性营养不良和亨廷顿病。虽然遗传证据指出DNA复制和/或修复错误是这些疾病的原因，但明确的分子机制尚未描述。在这里，我们关注错配修复复合体Msh2-Msh3在促进TNR扩展中的作用。我们证明Msh2-Msh3在酿酒酵母体内促进CTG和CAG重复扩增。此外，我们提供的生化证据表明，在TNR序列存在的情况下，Msh2-Msh3直接干扰皮瓣内切酶1 （Rad27）和DNA连接酶1 （Cdc9）对正常冈崎片段的加工，从而产生小的、增量的扩增事件。我们认为，这是第一个显示复制和修复蛋白在滞后链DNA复制过程中序列扩展中相互作用的机制证据。
Trinucleotide repeat (TNR) expansions are the underlying cause of more than 40 neurodegenerative and neuromuscular diseases, including myotonic dystrophy and Huntington's disease. Although genetic evidence points to errors in DNA replication and/or repair as the cause of these diseases, clear molecular mechanisms have not been described. Here, we focused on the role of the mismatch repair complex Msh2-Msh3 in promoting TNR expansions. We demonstrate that Msh2-Msh3 promotes CTG and CAG repeat expansions in vivo in Saccharomyces cerevisiae. Furthermore, we provide biochemical evidence that Msh2-Msh3 directly interferes with normal Okazaki fragment processing by flap endonuclease1 (Rad27) and DNA ligase I (Cdc9) in the presence of TNR sequences, thereby producing small, incremental expansion events. We believe that this is the first mechanistic evidence showing the interplay of replication and repair proteins in the expansion of sequences during lagging-strand DNA replication.