An Autonomous Clock that Controls Genetic Information Flow and Cellular Proteostasis

The central dogma of molecular biology, which delineates the flow of genetic information from DNA to RNA to proteins, is fundamental to cellular identity and functionality. This process involves intricate steps of transcription, mRNA processing, translation, and protein processing, each of which has been studied extensively over the past decades. Despite significant advancements in our understanding of these individual steps, the mechanisms by which these processes are spatiotemporally coordinated within each cell remain elusive. Efficient and precise transfer of genetic information is critical; any disruptions or "traffic jams" along this pathway including cryptic transcription, aberrant mRNA splicing, ribosome stalling, and protein misfolding and aggregation can lead to severe consequences such as aging and various diseases. Recently, our group has unveiled a cell-autonomous 12-h clock in mammalian cells that modulates the rhythmic activity of the entire genetic information flow. This discovery challenges the existing paradigm that genetic information flow is functioning at steady state but rather suggests that it oscillates with a robust 12-h cycle under normal physiological conditions, peaking at times of transition at dawn and dusk when metabolic stress is heightened. In this chapter, I will delve into the regulation, function, and evolutionary origins of the 12-h clock, and further elaborate how the 12-h clock can be utilized as a discovery tool to uncover hidden principles governing the spatiotemporal coordination of genetic information flow. Special attention will be given to the role of phase separation in facilitating this coordination, highlighting its significance in ensuring the seamless flow of genetic information across various cellular compartments and organelles.