How the c-myc promoter works and why it sometimes does not

The c-myc promoter is regulated by scores of signals, transcription factors, and chromatin components. The logic integrating these multiple signals remains unexplored. Recent evidence suggests that activated MYC expression is regulated in several phases: 1) conventional transcription factors trigger transcription by the RNA polymerase II (pol II) paused within the proximal promoter region. Concurrently (and probably consequently), newly arrived chromatin-remodeling complexes mobilize a nucleosome masking the far upstream element (FUSE), 1.7-kb upstream of the P2 start site; 2) binding by FUSE-binding proteins (first FBP3, then FBP); and 3) FBP-interacting repressor (FIR) binds FUSE and returns transcription to basal or steady-state levels. The recruitment and release of the FBPs and FIR is governed by FUSE-DNA conformation, itself controlled by dynamic supercoils propagated behind pol II. The organization and operation of the c-myc promoter make it difficult to inactivate, but sensitive to disturbances (translocations, viral insertions, amplification, and mutation) that disrupt the fine-tuning seen at its normal chromosomal context.