Molecular basis of FIR-mediated c-myc transcriptional control.
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.
Cukier
Cyprian D
CD
Molecular Structure Division, Medical Research Council National Institute for Medical Research, London, UK.
Hollingworth
David
D
Martin
Stephen R
SR
Kelly
Geoff
G
Díaz-Moreno
Irene
I
Ramos
Andres
A
D018360:Crystallography, X-Ray; D004265:DNA Helicases / Q000378:metabolism; D005786:Gene Expression Regulation; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism*; D014158:Transcription, Genetic
D016271:Proto-Oncogene Proteins c-myc; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C410595:poly-U binding splicing factor 60KDa; D004265:DNA Helicases