Sequence context effect for hMSH2-hMSH6 mismatch-dependent activation
Sequence context effect for hMSH2-hMSH6 mismatch-dependent activation
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DOI：
10.1073/pnas.0808572106
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发表时间：
2009-03-17
影响因子：
11.1
通讯作者：
Fishel, Richard
中科院分区：
文献类型：
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作者：
Mazurek, Anthony;Johnson, Christopher N.;Fishel, Richard
许多DNA错配和损伤激活MutS同源物（MSH）ATP酶活性，这对错配修复（MMR）至关重要。我们已经发现，嵌入在含有对称3 '-嘌呤（2x 3'-嘌呤）的最近邻序列环境中的错配增强了hMSH 2-hMSH 6 ATP酶活化，而对称3 '-嘧啶（2x 3'-嘧啶）降低了hMSH 2-hMSH 6 ATP酶活化。3 '-嘌呤/嘧啶效应对于含G错配最为明显。类似的趋势遍及错配结合（K-D）和未结合的寡核苷酸的解链（T-m; Δ G）。然而，这些后一种措施并不能准确地预测MSH ATP酶激活的层次结构。核磁共振研究亚氨基质子寿命，溶剂的可及性，和NOE连接表明，序列的情况下，挑起改善的MSH激活显示增强局部DNA的灵活性：一个动态的DNA签名，可以解释广泛的病变，激活MSH功能。
Numerous DNA mismatches and lesions activate MutS homologue (MSH) ATPase activity that is essential for mismatch repair (MMR). We have found that a mismatch embedded in a nearest-neighbor sequence context containing symmetric 3'-purines (2x3'-purines) enhanced, whereas symmetric 3'-pyrimidines (2x3'-pyrimidines) reduced, hMSH2-hMSH6 ATPase activation. The 3'-purine/pyrimidine effect was most evident for G-containing mispairs. A similar trend pervaded mismatch binding (K-D) and the melting of unbound oligonucleotides (T-m; Delta G). However, these latter measures did not accurately predict the hierarchy of MSH ATPase activation. NMR studies of imino proton lifetime, solvent accessibility, and NOE connectivity suggest that sequence contexts that provoke improved MSH-activation displayed enhanced localized DNA flexibility: a dynamic DNA signature that may account for the wide range of lesions that activate MSH functions.