Hypertranscription: the invisible hand in cancer epigenetics

Abstract Global upregulation of transcription, or hypertranscription, is observed in most human cancers, driven by the action of oncogene-encoded transcription factors (TFs). TF interactions with RNA Polymerase II (Pol II) are mediated by kinases that phosphorylate the Pol II C-terminal domain (CTD) to drive productive elongation. The combinatorial complexity of hundreds of transcription factors and kinases acting on thousands of genes that differ in expression between cell types obscures common features that may result from hypertranscription. One of these features is histone overexpression, which can accelerate cell-cycle progression and cause transcription-replication conflicts, triggering chromosomal instability. Pol II profiling provides a direct measure of hypertranscription and histone gene upregulation in cancer, a pan-cancer diagnostic to stratify patient populations and follow the course of treatment. As many broadly effective anticancer drugs target Pol II activity, a better understanding of how they counteract hypertranscription has implications for drug development and for improved treatment regimens. Here we review the underlying mechanisms that drive hypertranscription and its impact on chromosome integrity, aging and neoplasia.