Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, NY 14642, USA.
Cell Rep. 2012 Aug 30;2(2):216-22. doi: 10.1016/j.celrep.2012.06.020. Epub 2012 Aug 2.
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.
三核苷酸重复（TNR）扩展是 40 多种神经退行性和神经肌肉疾病的根本原因，包括肌营养不良症和亨廷顿病。尽管遗传证据表明 DNA 复制和/或修复错误是这些疾病的原因，但尚未描述明确的分子机制。在这里，我们专注于错配修复复合物 Msh2-Msh3 在促进 TNR 扩展中的作用。我们证明 Msh2-Msh3 在体内促进酿酒酵母中的 CTG 和 CAG 重复扩展。此外，我们提供生化证据表明，在 TNR 序列存在的情况下，Msh2-Msh3 通过 flap endonuclease1（Rad27）和 DNA 连接酶 I（Cdc9）直接干扰正常的 Okazaki 片段处理，从而产生小的、增量扩展事件。我们相信，这是第一个机制证据，表明复制和修复蛋白在滞后链 DNA 复制过程中序列扩展中的相互作用。
