The FUSE/FBP/FIR/TFIIH system is a molecular machine programming a pulse of c-myc expression

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Abstract
FarUpStream Element (FUSE) Binding Protein (FBP) binds the human c‐myc FUSE in vitro only in single‐stranded or supercoiled DNA. Because transcriptionally generated torsion melts FUSE in vitro even in linear DNA, and FBP/FBP Interacting Repressor (FIR) regulates transcription through TFIIH, these components have been speculated to be the mechanosensor (FUSE) and effectors (FBP/FIR) of a real‐time mechanism controlling c‐myc transcription. To ascertain whether the FUSE/FBP/FIR system operates according to this hypothesis in vivo , the flux of activators, repressors and chromatin remodeling complexes on the c‐myc promoter was monitored throughout the serum‐induced pulse of transcription. After transcription was switched on by conventional factors and chromatin regulators, FBP and FIR were recruited and established a dynamically remodeled loop with TFIIH at the P2 promoter. In XPB cells carrying mutant TFIIH, loop formation failed and the serum response was abnormal; RNAi depletion of FIR similarly disabled c‐myc regulation. Engineering FUSE into episomal vectors predictably re‐programmed metallothionein‐promoter‐driven reporter expression. The in vitro recruitment of FBP and FIR to dynamically stressed c‐myc DNA paralleled the in vivo process.