Regulation of RNA polymerase II transcription at gene 3-ends by CDK7 kinase

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 next generation of scientists to help maintain America's competitive edge in the biological, computational, and biomedical sciences. The experimental and educational plans are multi-disciplinary, involving computer science, mathematics, biochemistry, biophysics, cell biology, 3D animation, and science education. Objective 1 seeks to uncover how CDK7 kinase function controls RNAPII termination and/or RNA 3'-end processing, using a combination of transcriptomics, proteomics, in vitro biochemistry, smTIRF microscopy, cell biology and computational methods. Objective 2 probes whether common cellular responses to environmental stress mimic CDK7-inhibition conditions, and how CDK7 contributes to transcriptional stress responses. The results could reveal a completely new set of functions for CDK7, an important kinase that is conserved throughout eukaryotic evolution. Objective 3 addresses educational and training goals. The team will develop educational modules that address content gaps in undergraduate biochemistry textbooks and online resources, engage in outreach to local high schools, and train PhD students to become independent scientists who contribute to society in meaningful ways. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2546548 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Dylan Taatjes | Institution: University of Colorado at Boulder, BOULDER, CO | Award Amount: $1,493,073 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2546548 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2546548.html