Abstract 640: Human MutS homologue 4 (hMSH4) interacts with eIF3f and inhibits NHEJ-mediated DNA repair.

Abstract

Abstract DNA mismatch repair (MMR) proteins participate in diverse cellular functions including DNA damage response and repair. As a member of the MMR family, hMSH4 plays an important role in meiotic recombination, likely through the formation of hMSH4-hMSH5 heterocomplex that interacts with homologous recombination DNA intermediate structures. It is known that hMSH4 is expressed in an array of somatic cells; however, its involvement in mitotic processes is poorly defined. We have identified a new hMSH4 interacting partner eIF3f, a protein that functions not only in translation but also in the regulation of apoptosis and tumorigenesis. Our studies have demonstrated that hMSH4-eIF3f interaction is mediated through the N-terminal regions of both proteins. The interaction with eIF3f stabilizes hMSH4 protein, which in turn sustains DNA double strand break (DSB)-induced γ-H2AX foci and compromises cell survival in response to ionizing radiation (IR). These effects could be attributed to the inhibition of NHEJ activity by hMSH4. Furthermore, hMSH4 reduces IR-induced AKT activation, thereby facilitating eIF3f-mediated bypass of S phase arrest, and ultimately promoting G2/M arrest in response to IR treatment. In short, this study revealed a potential role of hMSH4 in the maintenance of genomic stability through suppressing error-prone DSB repair. Citation Format: Xiling Wu, Yen-Lin Chu, Chengtao Her. Human MutS homologue 4 (hMSH4) interacts with eIF3f and inhibits NHEJ-mediated DNA repair. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 640. doi:10.1158/1538-7445.AM2013-640