Professor
Ph.D., Harvard University, 1986

Posttranscriptional control of gene expression; alternative splicing; splicing in genetic diseases and cancer; splicing-targeted antisense therapeutics

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RNA splicing is required for expression of most eukaryotic protein-coding genes. For many of these genes, alternative splicing regulates the production of multiple isoforms. Splicing requires >200 proteins and five snRNAs that assemble into a macromolecular machine, the spliceosome. We use multidisciplinary approaches to study splicing mechanisms and regulation.

A major focus is the study of the detailed structures, posttranslational modifications, RNA-binding, and functions of selected factors, as well as their mechanisms of action in vivo. In particular, we study the human SR and hnRNP A/B protein families, members of which interact combinatorially to modulate the selection of many alternative splice sites. Individual SR proteins, such as SRSF1, are also required for spliceosome assembly. We are interested in their specificity in recognition of exonic or intronic elements that dictate splicing efficiency and alternative splicing patterns. We recently demonstrated that SRSF1 is an oncoprotein, and we are investigating how this class of proteins control cell proliferation and differentiation.

We also investigate how point mutations in exons or introns result in aberrant splicing, leading to numerous genetic diseases. We have focused on the SMN1/2 genes associated with a neuromuscular disease, spinal muscular atrophy. We have developed methods to correct defective splicing, for both mechanistic studies and therapeutic applications, and have already demonstrated antisense-oligonucleotide-mediated splicing correction of human SMN2 in transgenic SMA mouse models, resulting in phenotypic rescue.

 

Selected Publications

Hua, Y., Sahashi, K., Hung, G., Rigo, F., Passini, M.A., Bennett, C.F., and Krainer, A.R. 2010. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 24: 1634–1644.

Sun, S., Zhang, Z., Sinha, R., Karni, R., and Krainer, A.R. 2010. SF2/ASF autoregulation involves multiple layers of post-transcriptional and translational control. Nat. Struct. Mol. Biol. 17: 306–312.

Clower, C.V., Chatterjee, D., Wang, Z., Cantley, L.C., Vander Heiden, M.G., and Krainer, A.R. 2010. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc. Natl. Acad. Sci. USA 107: 1894–1899.

Roca, X. and Krainer, A.R. 2009. Recognition of atypical 5' splice sites by shifted base-pairing to U1 snRNA. Nat. Struct. Mol. Biol. 16: 176–182.

Hastings, M.L., Berniac, J., Liu, Y.H., Abato, P., Jodelka, F.M., Barthel, L., Kumar, S., Dudley, C., Nelson, M., Larson, K., Edmonds, J., Bowser, T., Draper, M., Higgins, P., and Krainer, A.R. 2009. Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for spinal muscular atrophy. Science Transl. Med. 1: 5ra12.