Research / Clinical Summary

Xiang-Dong Fu, PhD Professor, Medicine / Cellular & Molecular Medicine Cancer Biology Program Contact by Email

Research in my lab centers on the mechanisms and regulation of pre-mRNA splicing in eukaryotic cells. Splicing represents one of the major post-transcriptional events in the nucleus. Spliced RNA is then exported to the cytoplasm to act as a template for protein synthesis. Most genes in higher eukaryotic cells contain multiple exons separated by introns which can be as long as 100 kb. Thus, the splicing machinery must be precise and efficient in selecting functional splice sites and distinguishing them from other similar RNA elements and/or structures. This splice site selection process is accomplished by a series of specific RNA-RNA, protein-RNA, and protein-protein interactions between pre-mRNA and small nuclear ribonucleoproteins (snRNPs) and non-snRNP splicing factors. Although splicing can take place in cell free extracts, the efficiency of splicing and the prevention of both exon skipping and premature transport of unprocessed RNA to the cytoplasm may be further ensured by efficient coupling between transcription and splicing and between splicing and RNA export. Finally, numerous transcripts in higher eukaryotic cells are alternatively processed to give rise to multiple mRNAs. In many cases, alternatively spliced mRNAs encode proteins with distinct functions. Consequently, deregulation of alternative splicing has been attributed to or correlated with a number of developmental disorders and cancers. Thus, gene expression must be critically regulated at the RNA processing level.

Our research effort has been devoted to the functional studies of the SR (for serine and arginine-rich) family of non-snRNP splicing factors, and to the regulation of SR proteins by phosphorylation. SR proteins are RNA binding proteins that play a critical role in initiating complex assembly on pre-mRNA. Remarkably, SR proteins are not only essential for constitutive splicing, but also affect alternative splicing both in vitro and in vivo. To understand the mechanism and specificity of SR proteins, we have focused on characterizing model SR proteins with regard to their interaction with specific RNA elements in pre-mRNA and with other splicing factors in the assembly of specific splicing complexes. More recently, it was showed that SR protein-protein interactions are mediated by their serine and arginine-rich domains and the interactions appear to be regulated by phosphorylation. Our group has cloned and characterized the first protein kinase specific for SR proteins. We have discovered that the kinase mediates both intracellular targeting and specific SR protein-protein interactions. Furthermore, both phosphorylation of SR proteins and the kinase itself appear to be cell cycle regulated. We are now taking a combination of genetic, molecular and biochemical approaches to investigate how SR protein specific kinases might be involved in the regulation of alternative splicing, and how the kinases themselves are regulated by internal and external signals.

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