email krainer@cshl.edu, phone (516) 367-8417, fax (516) 367-8453

RNA splicing is required for expression of most eukaryotic protein-coding genes. For many such genes, alternative splicing regulates the production of multiple isoforms. Splicing requires numerous proteins and small RNAs that assemble into a macromolecular machine, the spliceosome. We use biochemical and molecular approaches to study the mechanisms and regulation of splicing.

A major effort in our lab is the identification and characterization of human proteins involved in the two catalytic steps of splicing or in regulating alternative splicing. We study the detailed structure, function, posttranslational modification, and specific RNA-binding or other functional properties of selected protein factors, as well as their subcellular localization and mechanisms of action in vivo. For example, we study the human SR (serine/arginine-rich) and hnRNP (heterogeneous nuclear ribonucleoprotein) A/B protein families. The members of these families interact antagonistically to modulate the selection of alternative splice sites. Individual SR proteins, such as SF2/ASF, are also required for spliceosome assembly. We are interested in their mechanism of action and their specificity in the recognition of exonic splicing enhancer and silencer elements, which are important for splice-site selection and splicing efficiency. We have recently demonstrated that SF2/ASF is an oncoprotein.

We also investigate the mechanisms by which single point mutations in exons result in exon skipping, leading to many genetic diseases. In particular, we have focused on the SMN genes, which are involved in spinal muscular atrophy. We are pursuing the rational design of specific compounds to suppress exon skipping, for both mechanistic studies and potential therapeutic applications.