Ph.D., Harvard University, 1986
Posttranscriptional control of gene expression; alternative splicing; splicing in genetic diseases and cancer; splicing-targeted antisense therapeutics
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, as well as in their additional functions. We 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 developed antisense methods for targeted manipulation of splicing, for both mechanistic studies and therapeutic applications, and have already achieved efficient splicing correction of human SMN2 in transgenic SMA mouse models, resulting in phenotypic rescue. This work provided the basis for ongoing clinical trials, currently in phase 2.
Selected PublicationsFregoso, O.I., Das, S., Akerman, and M., Krainer, A.R. 2013. Splicing-factor oncoprotein SRSF1 stabilizes p53 via RPL5 and induces cellular senescence. Mol Cell 50: 56–66.
Sahashi, K., Hua, Y., Ling, K.K., Hung, G., Rigo, F., Horev, G., Katsuno, M., Sobue, G., Ko, C.P., Bennett, C.F., and Krainer, A.R. 2012. TSUNAMI: an antisense method to phenocopy splicing-associated diseases in animals. Genes Dev. 26: 1874–1884.
Roca, X., Akerman, M., Gaus, H., Berdeja, A., Bennett, C.F., and Krainer, A.R. 2012. Widespread recognition of 5' splice sites by noncanonical base-pairing to U1 snRNA involving bulged nucleotides. Genes Dev. 26: 1098–1109.
Das, S., Anczuków, O., Akerman, M., and Krainer, A.R. 2012. Oncogenic splicing factor SRSF1 is a critical transcriptional target of MYC. Cell Rep. 1: 110–117.
Hua, Y., Sahashi, K., Rigo, F., Hung, G., Horev, G., Bennett, C.F., and Krainer, A.R. 2011. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478: 123–126.