The interplay between hMLH1 and hMRE11: role in MMR and the effect of hMLH1 mutations.
The interplay between hMLH1 and hMRE11: role in MMR and the effect of hMLH1 mutations.
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DOI：
10.1016/j.bbrc.2008.03.082
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发表时间：
2008-05
影响因子：
3.1
通讯作者：
N. Zhao;Fengxue Zhu;F. Yuan;A. Haick;S. Fukushige;L. Gu;C. Her
中科院分区：
文献类型：
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作者：
N. Zhao;Fengxue Zhu;F. Yuan;A. Haick;S. Fukushige;L. Gu;C. Her
我们之前的研究表明，hMRE11 在 MMR 中发挥作用，并且 hMRE11 的这种功能很可能是由 hMLH1-hMRE11 相互作用介导的。在这里，我们探讨了 hMLH1-hMRE11 相互作用在 MMR 中的功能意义以及 hMLH1 突变对其相互作用的影响。我们的体外 MMR 测定表明，显性失活 hMRE11452-634 突变肽（即仅包含 hMLH1 相互作用结构域）显着降低了 3' 切除和 3' 定向 MMR 活性。此外，hMRE11452-634 以及较小程度的 hMRE111-634(ATLD1) 的表达，损害了 MNU 和顺铂治疗对 G2/M 检查点的控制，使细胞对这两种抗癌药物的杀伤产生抵抗力。对 38 个 hMLH1 错义突变的分析表明，大多数突变导致其与 hMRE11 的相互作用显着降低 (>50%)，这表明异常蛋白相互作用与 hMLH1 变体的致病作用之间存在潜在联系。
Our previous studies indicate that hMRE11 plays a role in MMR, and this function of hMRE11 is most likely mediated by the hMLH1–hMRE11 interaction. Here, we explored the functional implications of the hMLH1–hMRE11 interaction in MMR and the effects of hMLH1 mutations on their interaction. Our in vitro MMR assay demonstrated that the dominant-negative hMRE11452–634mutant peptide (i.e., harboring only the hMLH1-interacting domain) imparted a significant reduction in both 3′ excision and 3′-directed MMR activities. Furthermore, the expression of hMRE11452–634, and to a lesser extent hMRE111–634(ATLD1), impaired G2/M checkpoint control in response to MNU and cisplatin treatments, rendering cells resistant to killings by these two anticancer drugs. Analysis of 38 hMLH1 missense mutations showed that the majority of mutations caused significant (>50%) reductions in their interaction with hMRE11, suggesting a potential link between aberrant protein interaction and the pathogenic effects of hMLH1 variants.