Nuclear transcription machinery

The nuclear transcription machinery is a complex multi-protein system responsible for the synthesis of messenger RNA (mRNA) and most small nuclear RNAs from DNA templates. This machinery primarily centers around RNA polymerase II (Pol II) and includes an array of general transcription factors, co-activators like the Mediator complex, and various chromatin remodelers (Sainsbury et al., 2015). In healthy cells, this apparatus is tightly regulated to ensure precise spatio-temporal gene expression; however, in many cancers, the machinery is co-opted by oncogenes to drive aberrant transcriptional programs (Bradner et al., 2017). Pharmacological targeting of the transcription machinery has evolved from non-specific DNA intercalators like actinomycin D to more selective inhibitors of transcriptional kinases such as CDK7 and CDK9 (Bushweller, 2019). These inhibitors aim to disrupt the transcriptional addiction of cancer cells, particularly those dependent on high levels of short-lived oncogenic proteins like MYC. Despite their clinical potential, these agents often carry significant safety risks, including systemic toxicity and myelosuppression, due to the fundamental requirement of transcriptional activity for all normal cells (Ott et al., 2018).

Other names

Transcriptional apparatusRNA polymerase II transcription machineryPre-initiation complexTranscriptional machineryPol II machinery

Inhibition of RNA polymerase II catalytic activity, inhibition of transcriptional cyclin-dependent kinases (CDK7, CDK8, CDK9), DNA intercalation blocking polymerase progression, and degradation of RNA polymerase II subunits.