LAUSR

Simple Summary Building ribosomes for cellular protein translation is a massive, energy-consuming undertaking. The process is executed by all cells to replenish the relevant pools of proteins required for cellular functions. Cancer cells are strikingly dependent on this activity, as they need continuous protein synthesis for sustained proliferation and growth. Ribosome biogenesis requires the activities of three RNA polymerases, which transcribe essential RNAs that make up the backbone of the ribosome, and hundreds of proteins, which provide structural and functional support. Of the three RNA polymerases, RNA polymerase I executes a critical and rate-limiting step by transcribing three key ribosomal RNAs. Pol I transcription is pervasively deregulated in cancers, enabling unlimited protein synthesis. Here, we review this enzyme and provide examples of current efforts to target Pol I transcription therapeutically. Abstract RNA polymerase I is a highly processive enzyme with fast initiation and elongation rates. The structure of Pol I, with its in-built RNA cleavage ability and incorporation of subunits homologous to transcription factors, enables it to quickly and efficiently synthesize the enormous amount of rRNA required for ribosome biogenesis. Each step of Pol I transcription is carefully controlled. However, cancers have highjacked these control points to switch the enzyme, and its transcription, on permanently. While this provides an exceptional benefit to cancer cells, it also creates a potential cancer therapeutic vulnerability. We review the current research on the regulation of Pol I transcription, and we discuss chemical biology efforts to develop new targeted agents against this process. Lastly, we highlight challenges that have arisen from the introduction of agents with promiscuous mechanisms of action and provide examples of agents with specificity and selectivity against Pol I.