Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics, The Ohio State University and The Ohio State University Medical Center, Columbus, 43210, USA.
Mol Cell. 2009 Dec 25;36(6):1086-94. doi: 10.1016/j.molcel.2009.12.010.
DNA nucleotide mismatches and lesions arise on chromosomes that are a complex assortment of protein and DNA (chromatin). The fundamental unit of chromatin is a nucleosome that contains approximately 146 bp DNA wrapped around an H2A, H2B, H3, and H4 histone octamer. We demonstrate that the mismatch recognition heterodimer hMSH2-hMSH6 disassembles a nucleosome. Disassembly requires a mismatch that provokes the formation of hMSH2-hMSH6 hydrolysis-independent sliding clamps, which translocate along the DNA to the nucleosome. The rate of disassembly is enhanced by actual or mimicked acetylation of histone H3 within the nucleosome entry-exit and dyad axis that occurs during replication and repair in vivo and reduces DNA-octamer affinity in vitro. Our results support a passive mechanism for chromatin remodeling whereby hMSH2-hMSH6 sliding clamps trap localized fluctuations in nucleosome positioning and/or wrapping that ultimately leads to disassembly, and highlight unanticipated strengths of the Molecular Switch Model for mismatch repair (MMR).
DNA 核苷酸错配和损伤出现在由蛋白质和 DNA（染色质）组成的复杂混合物的染色体上。染色质的基本单位是核小体，它包含大约 146bp 的 DNA 缠绕在一个 H2A、H2B、H3 和 H4 组蛋白八聚体周围。我们证明，错配识别异二聚体 hMSH2-hMSH6 可使核小体解体。解组装需要一个错配，引发 hMSH2-hMSH6 水解非依赖性滑动夹的形成，这些滑动夹沿着 DNA 转移到核小体。解组装的速度通过核小体进入-退出和二联体轴内组蛋白 H3 的实际或模拟乙酰化增强，这种乙酰化发生在体内复制和修复过程中，并降低体外 DNA-八聚体亲和力。我们的结果支持染色质重塑的被动机制，其中 hMSH2-hMSH6 滑动夹捕获核小体定位和/或缠绕的局部波动，最终导致解组装，并突出了错配修复（MMR）分子开关模型的意外优势。
