Reduced TOP1 activity potentiates MYC transcription amplification in cell and biochemical assays
Authors built a system separating MYC-driven activation from amplification and linked amplification to DNA supercoiling. Findings come from cellular and biochemical assays.
Researchers report in the Proceedings of the National Academy of Sciences a system that distinguishes MYC-driven transcription activation from amplification in any cell pnas.org
Proceedings of the National Academy of Sciencespnas.orgOpen source ↗. Dysregulated MYC causes profound changes in gene expression in cancer. It is usually considered an E-box-dependent transcription activator, while an alternative model treats it as a universal amplifier of transcription.
The system allows the authors to examine genes, cofactors and compounds that execute or modulate MYC activity. Using biochemical and cellular assays, they describe a dynamic interplay between MYC-driven transcription amplification and DNA supercoiling. MYC is known to stimulate topoisomerases to resolve DNA topological problems that complicate its work. How this stimulation is coordinated with its transcriptional role had not been examined.
Reducing TOP1 activity, either by genetic knockdown or by low-dose inhibition, potentiates transcription amplification by MYC. The early stages of transcription are sensitive to DNA supercoiling. According to the authors, negative supercoiling increases promoter melting and RNA polymerase loading. This provides the early transcription complexes on which MYC acts to increase output.
