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首页> 外文期刊>Molecular Cancer >MutS homologue hMSH4: interaction with eIF3f and a role in NHEJ-mediated DSB repair
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MutS homologue hMSH4: interaction with eIF3f and a role in NHEJ-mediated DSB repair

机译：MutS同源物hMSH4：与eIF3f相互作用并在NHEJ介导的DSB修复中起作用

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Background 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). Results 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. Conclusion Our current study has revealed a role for hMSH4 in the maintenance of genomic stability by suppressing NHEJ -mediated DSB repair.
机译：背景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。作为该蛋白质家族的成员，hMSH4在有丝分裂细胞中的分子机制尚不清楚。众所周知，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。结果我们鉴定了一种新的hMSH4相互作用蛋白eIF3f，该蛋白不仅在翻译中起作用，而且在人类凋亡和肿瘤发生的调节中起作用。我们的研究表明，hMSH4-eIF3f相互作用是通过两种蛋白质的N端区域介导的。与eIF3f的相互作用促进了hMSH4蛋白质的稳定，继而维持了γ-H2AX病灶并响应电离辐射（IR）诱导的DNA损伤而损害了细胞存活。这些作用可以至少部分归因于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期阻滞的旁路，并最终增强了对IR治疗的早期G2 / M阻滞。结论我们目前的研究揭示了hMSH4通过抑制NHEJ介导的DSB修复在维持基因组稳定性中的作用。

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