Research Description:

We are interested in understanding how signal transduction pathways regulate gene expression and development.  There are currently three projects in the laboratory that explore this interest.

Project 1: Signal-dependent regulation of alternative splicing.
Alternative splicing is the process by which pre-mRNA exons are differentially ligated together to produce different mature mRNAs.  The coupling of signal transduction pathways to alternative splicing is predicted to be a major mechanism for regulating gene expression during development and in response to altered physiological or pathological conditions.  Recent estimates based on genomic analyses indicate that ~75% of human pre-mRNAs are alternatively spliced.  Alternative splicing can generate multiple, distinct mRNAs from a single gene and each distinct mRNA can potentially encode a functionally distinct protein.  Accordingly, alternative splicing affects basic cellular processes such as transcription and apoptosis, and mistakes in alternative splicing underlie human diseases such as autoimmune diseases and many types of cancer.  While documented examples of changes in splicing pattern in response to extracellular stimuli are plentiful, little is known about the mechanisms by which signaling events modulate the activity of the splicing machinery.

To learn about the mechanisms that underlie signal-dependent alternative splicing, we are using Drosophila as a model organism to understand how signals induced by DNA damage regulate alternative splicing of the TAF1 (TBP-associated factor 1) pre-mRNA (Figure 1).  To date, these studies have identified the ATM and ATR signaling pathways as transducers of the DNA damage signal to the splicing machinery that regulates TAF1 alternative splicing (Katzenberger et al. 2006).  Ongoing genetic and molecular studies are aimed at identifying cis-acting pre-mRNA sequences and trans-acting splicing regulatory proteins that are targets of these signals.

Research Interests: Cell cycle progression and DNA replication, viral manipulation of the cell cycle, HCMV replication and pathogenesis, Rb/E2F pathway, ubiquitin-mediated proteolysis, HCMV genetics.

Research Focus: My lab focuses on the mechanisms of mammalian cell cycle progression, and uses human cytomegalovirus as a tool to probe the pathways that lead to oncogenesis. As obligate intracellular parasites, viruses are reliant upon their host cells for their replication, and have evolved ways to commandeer cellular pathways to promote their own survival. Studies of viral regulation of the cell cycle have led to major advances in the field of cell cycle research, including the discovery of oncogenes, the p53 tumor suppressor, and the E2F family of transcription factors, as well as elucidating the role of the retinoblastoma (Rb) family of tumor suppressors in cellular growth control.

Human cytomegalovirus (HCMV) alters the cell cycle in a very unique way. It induces quiescent (G0) cells to re-enter the cell cycle, travel through G1, but then arrests them at the G1/S border before the cell begins to replicate its own DNA. This cell cycle position is favorable for efficient viral replication since all of the building blocks for DNA replication are present but are not being consumed by the host cell for the synthesis of its own genome.