School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Mail Drop 64-7520, Pullman, WA 99164, USA.
Mol Cancer. 2013 Jun 2;12:51. doi: 10.1186/1476-4598-12-51.
DNA mismatch repair proteins participate in diverse cellular functions including DNA damage response and repair. As a member of this protein family, the molecular mechanisms of hMSH4 in mitotic cells are poorly defined. It is known that hMSH4 is promiscuous, and among various interactions the hMSH4-hMSH5 interaction is involved in recognizing DNA intermediate structures arising from homologous recombination (HR).
We identified a new hMSH4 interacting protein eIF3f--a protein that functions not only in translation but also in the regulation of apoptosis and tumorigenesis in humans. Our studies have demonstrated that hMSH4-eIF3f interaction is mediated through the N-terminal regions of both proteins. The interaction with eIF3f fosters hMSH4 protein stabilization, which in turn sustains γ-H2AX foci and compromises cell survival in response to ionizing radiation (IR)-induced DNA damage. These effects can be, at least partially, attributed to the down-regulation of NHEJ activity by hMSH4. Furthermore, the interplay between hMSH4 and eIF3f inhibits IR-induced AKT activation, and hMSH4 promotes eIF3f-mediated bypass of S phase arrest, and ultimately enhancing an early G2/M arrest in response to IR treatment.
Our current study has revealed a role for hMSH4 in the maintenance of genomic stability by suppressing NHEJ-mediated DSB repair.
DNA 错配修复蛋白参与多种细胞功能，包括 DNA 损伤反应和修复。作为该蛋白家族的一员，hMSH4 在有丝分裂细胞中的分子机制尚未明确。已知 hMSH4 是混杂的，在各种相互作用中，hMSH4-hMSH5 相互作用涉及识别同源重组（HR）产生的 DNA 中间结构。
我们鉴定了一个新的 hMSH4 相互作用蛋白 eIF3f——一种不仅在翻译中起作用，而且在人类细胞凋亡和肿瘤发生的调节中起作用的蛋白。我们的研究表明，hMSH4-eIF3f 相互作用是通过两种蛋白的 N 端区域介导的。与 eIF3f 的相互作用促进了 hMSH4 蛋白的稳定，这反过来又维持了 γ-H2AX 焦点，并损害了细胞对电离辐射（IR）诱导的 DNA 损伤的存活。这些效应至少部分归因于 hMSH4 对 NHEJ 活性的下调。此外，hMSH4 和 eIF3f 之间的相互作用抑制了 IR 诱导的 AKT 激活，hMSH4 促进了 eIF3f 介导的 S 期阻滞旁路，最终增强了对 IR 处理的早期 G2/M 阻滞。
我们目前的研究揭示了 hMSH4 通过抑制 NHEJ 介导的 DSB 修复来维持基因组稳定性的作用。
