title: MutS homologue hMSH4: interaction with eIF3f and a role in NHEJ-mediated DSB repair.
abstract: 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.
  
  
  CONCLUSIONS
  Our current study has revealed a role for hMSH4 in the maintenance of genomic stability by suppressing NHEJ-mediated DSB repair.
authors.affiliation: School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Mail Drop 64-7520, Pullman, WA 99164, USA.
authors.forename: Yen-Lin
authors.initials: YL
authors.lastname: Chu
authors.forename: Xiling
authors.initials: X
authors.lastname: Wu
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Chengtao
authors.initials: C
authors.lastname: Her
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D059766:DNA End-Joining Repair / Q000502:physiology*; D004789:Enzyme Activation / Q000528:radiation effects; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C584155:EIF3F protein, human; D039621:Eukaryotic Initiation Factor-3; C409221:MSH4 protein, human; D051057:Proto-Oncogene Proteins c-akt