This collaborative project focuses on an enzyme called CDK7, which is critical for all physiological processes (e.g., human development, growth, maintenance of normal cell function). Aberrant CDK7 activity contributes to developmental disorders and cancer; thus, understanding how CDK7 works has broad health implications and will advance molecular therapeutics. CDK7 controls how the human genome is decoded by RNA polymerase II (RNAPII), an enzyme that "reads" specific sections of DNA, which ultimately determines cellular function. RNAPII must start and stop reading at precise sites on DNA to avoid pathogenic outcomes (e.g. developmental disorders or cancer). CDK7 is known for its ability to direct RNAPII to specific "start" sites on DNA. This scientific team recently discovered that CDK7 controls RNAPII function at the "stop" sites as well. Furthermore, this discovery linked CDK7 function to cell stress responses (e.g., to elevated body temperature or viral/bacterial infections) and therefore has broad implications for biotechnology and biomedicine. In this project, the team will define how CDK7 performs the newly discovered functions in human cells, under normal and stress conditions. The outcomes are expected to yield fundamental insights about how cells respond to and recover from stress, and the knowledge will improve anti-cancer therapeutics and strategies to mitigate chronic stress. The project will also engage trainees from high school to graduate levels and foster the