David A. Schneider, Ph.D.
Associate Professor, Department of Biochemistry and Molecular Genetics
Areas of Focus: The overall goal of my lab is to define the molecular mechnaisms that control transcription of the ribosomal DNA by RNA polymerase I. We use a variety of experimental techniques and eukaryotic model systems in pursuit of this goal.
Transcription of the ribosomal DNA by RNA polymerase I (Pol I) is the first, rate-limiting step in ribosome biosynthesis. Recent studies using cell culture and pre-clinical animal models have demonstrated that inhibition of Pol I activity selectively inhibits cancer cell growth. Thus, characterization of Pol I transcription will expand our fundamental understanding of cell biology and inform ongoing development of novel chemotherapeutic strategies.
Our current interests include (but are not limited to):
- Kinetic analysis of WT and mutant Pol I transcription elongation properties. These projects will define the unique features of the enzyme and contributions of individual subunits to overall activity.
- Characterization of trans-acting factors that influence efficiency and/or regulation of Pol I transcription. We have identified roles in Pol I transcription for a number of proteins with previously described effects on Pol II.
- Defining the relationship between Pol I transcription elongation kinetics and processing of the nascent pre-rRNA. We know that transcription elongation by Pol I is functionally coupled to rRNA processing. These studies will identify Pol I features and DNA template features that influence efficiency pre-rRNA processing.
In addition to these core projects, the lab collaborates with a number of labs on campus and around the world. These collaborative works address a wide range of biological questions, but each is tied (one way or another) to ribosome biogenesis.
Our long-term goal is to fully characterize factors that regulate initiation and elongation steps in Pol I transcription. Without understanding the robust mechanisms that control and optimize transcription initiation and elongation by Pol I, the long known role for ribosome synthesis in cell transformation cannot be defined or controlled. Progress toward this goal requires rigorous biochemical and genetic study of all steps in transcription by Pol I.
One example of recent progress toward our overall goal is described in a collaborative study between the Schneider lab and the Kaplan lab (Texas A&M University; Viktorovskaya et al. Cell Reports, 2013). In that study, we characterized a collection of mutations in the highly conserved trigger loop domain of Pol I (panel A, accompanying figure). The trigger loop is a flexible domain that directly participates in nucleotide addition and is conserved among all multi-subunit RNA polymerases in all three domains of life. We found that a number of these mutations had opposite effects in Pol I than were described previously for Pol II. One mutant (E1224G in Pol I) resulted in slow transcription elongation (panel B, accompanying figure) whereas the identical mutation in Pol II increased the rate of transcription. These and other data led to the conclusion that Pol I and Pol II may have evolved unique enzymatic properties despite the high degree of sequence identity between the two enzymes.
Dr. Schneider was raised in the suburbs of Atlanta, GA. He obtained his B.S. in microbiology and genetics from the University of Georgia in 1998. As an undergraduate he studied molecular biology of bacteriophage. As a graduate student at the University of Wisconsin (1998 - 2003), he moved up the tree of life to study the effect of small molecule regulators on transcription in bacteria. For his postdoctoral studies at the University of California, Irvine (2003 - 2007), he inched further up the tree of life to study the molecular mechanisms by which RNA polymerase I is regulated in eukaryotic cells. His work continues to focus on studies in model eukaryotic cells (yeast and mammalian cell culture). Dr. Schneider joined the faculty as an Assistant Professor at UAB in 2007 and was promoted to Associate Professor in 2013.