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

Mol Cancer. 2013 Jun 2;12:51. doi: 10.1186/1476-4598-12-51.

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.

Conclusion: Our current study has revealed a role for hMSH4 in the maintenance of genomic stability by suppressing NHEJ-mediated DSB repair.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Cycle Checkpoints / genetics
  • Cell Cycle Checkpoints / radiation effects
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Cell Survival / genetics
  • Cell Survival / radiation effects
  • DNA End-Joining Repair / physiology*
  • Enzyme Activation / radiation effects
  • Eukaryotic Initiation Factor-3 / genetics
  • Eukaryotic Initiation Factor-3 / metabolism*
  • Humans
  • Protein Binding
  • Protein Stability
  • Proto-Oncogene Proteins c-akt / metabolism

Substances

  • Cell Cycle Proteins
  • EIF3F protein, human
  • Eukaryotic Initiation Factor-3
  • MSH4 protein, human
  • Proto-Oncogene Proteins c-akt