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

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.
Mesh Terms:
Cell Cycle Checkpoints, Cell Cycle Proteins, Cell Line, Cell Survival, DNA End-Joining Repair, Enzyme Activation, Eukaryotic Initiation Factor-3, Humans, Protein Binding, Protein Stability, Proto-Oncogene Proteins c-akt
Mol. Cancer
Date: Jun. 04, 2013
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