MutS homologue hMSH4: interaction with eIF3f and a role in NHEJ-mediated DSB repair

Molecular Cancer

Research

Xiling Wu¹  Yang Xu¹  Yen-Lin Chu¹  Chengtao Her¹ 

[1] School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Mail Drop 64–7520, 99164, Pullman, WA, USA;

关键词: hMSH4;    eIF3f;    Ionizing radiation (IR);    Non-homologous end-joining (NHEJ);   

DOI  :  10.1186/1476-4598-12-51

 received in 2012-11-01, accepted in 2013-05-31,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundDNA 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).ResultsWe 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.ConclusionOur current study has revealed a role for hMSH4 in the maintenance of genomic stability by suppressing NHEJ-mediated DSB repair.

【 授权许可】

Unknown   
© Chu et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.