Beyond gene ends: The expanding roles of transcription termination in genome stability and cellular homeostasis

Gene expression is determined by the right region and at the right time to shape a cellular function. To understand the landscape of gene expression, large-scale transcriptomic analyses for transcription start sites (where to start) have been employed. However, transcription termination sites (where to stop) and the regulatory mechanisms involved remain largely unclear. Recent studies with state-of-the-art technologies have revealed that RNA polymerase II (Pol II) termination sites are not exact gene ends, but rather within broad downstream-of-gene (DoG) regions. Restriction of DoG transcription contributes to efficient mRNA synthesis, whereas excessive or persistent DoG transcription caused by transcription termination defects blocks DNA replication and produces immunogenic nucleic acids. This review summarizes the latest findings on molecular mechanisms and biological impacts of Pol II transcription termination, and methodologies to investigate them. Finally, we discuss a potential application of Pol II transcription termination regulation for future research directions.