Research

Understanding how mRNA levels are controlled in eukaryotes requires dissection of the intricate pathway responsible for the synthesis and processing of mRNA. Previously, we obtained evidence for a general eukaryotic transcription regulatory process that controls the number of polymerase molecules that are able to produce full-length mRNAs. We discovered P-TEFb, a cyclin dependent kinase that plays a key role in this elongation control process. The kinase activity of P-TEFb is generally required for eukaryotic gene expression and recent results indicate that cells carefully regulate P-TEFb through an unusual association with a 7SK snRNP containing HEXIM1, MEPCE, and LARP7. We are currently engaged in projects to uncover the mechanism of P-TEFb function and how it is regulated in both humans and Drosophila. Our basic research on factors that influence elongation by RNA polymerase II also uncovered the first RNA polymerase II termination factor, TTF2. This factor plays a role in mitotic repression of transcription elongation and, perhaps, DNA repair. Finally, we have developed new in vitro assays to study the mechanistic details of the interaction of RNA processing machinery with the transcription complex. We have shown that 5' capping of mRNAs occurs about 100,000 times more efficiently if transcripts are in elongation complexes. Also coupling of cleavage and polyadenylation of mRNAs is much more efficient on nascent RNA. Overall, we use biochemical, molecular and cellular techniques to advance our understanding of the control of RNA polymerase II elongation and how that process influences RNA processing, HIV replication and cancer growth.