Molecular basis of FIR-mediated c-myc transcriptional control

Nat Struct Mol Biol. 2010 Sep;17(9):1058-64. doi: 10.1038/nsmb.1883. Epub 2010 Aug 15.

Abstract

The far upstream element (FUSE) regulatory system promotes a peak in the concentration of c-Myc during cell cycle. First, the FBP transcriptional activator binds to the FUSE DNA element upstream of the c-myc promoter. Then, FBP recruits its specific repressor (FIR), which acts as an on/off transcriptional switch. Here we describe the molecular basis of FIR recruitment, showing that the tandem RNA recognition motifs of FIR provide a platform for independent FUSE DNA and FBP protein binding and explaining the structural basis of the reversibility of the FBP-FIR interaction. We also show that the physical coupling between FBP and FIR is modulated by a flexible linker positioned sequentially to the recruiting element. Our data explain how the FUSE system precisely regulates c-myc transcription and suggest that a small change in FBP-FIR affinity leads to a substantial effect on c-Myc concentration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • DNA Helicases / metabolism
  • Gene Expression Regulation*
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Interaction Domains and Motifs
  • Protein Structure, Quaternary
  • Proto-Oncogene Proteins c-myc / genetics*
  • RNA Splicing Factors
  • RNA-Binding Proteins
  • Repressor Proteins / chemistry*
  • Repressor Proteins / metabolism*
  • Transcription, Genetic*

Substances

  • Proto-Oncogene Proteins c-myc
  • RNA Splicing Factors
  • RNA-Binding Proteins
  • Repressor Proteins
  • poly-U binding splicing factor 60KDa
  • DNA Helicases

Associated data

  • PDB/2KXF
  • PDB/2KXH