Mechanism and Regulation of the U12-dependent spliceosome



Our main interest is post-transcriptional gene regulation in various eukaryotic model systems. In particular we are interested in pre-mRNA splicing, in which the noncoding intron sequences are removed from the pre-mRNA molecules by the spliceosome. This process is necessary for the formation of functional mRNA molecules, but is also an important control point regulating eukaryotic gene expression. The other focus of our lab is to study gene expression and allelic variation of in natural populations of such animal species that are not laboratory model organisms.

Our studies of pre-mRNA splicing are centered on the U12-dependent spliceosome (so called "minor spliceosome") which is thought regulate gene expression mostly by adjusting the cellular level of individual mRNAs rather than controlling the mRNA information content by alternative splicing. The targets of this splicing machinery are a class of rare introns, called U12-type introns. These introns have recognition sequences that are longer and much more conserved than the ones from the standard U2-type introns. These sequences are removed by a separate U12-dependent spliceosome, while the majority of introns are excised by U2-dependent spliceosome. In humans there are approximately 600 U12-type introns belonging mostly to so called "information processing" gene group, which is linked to important cellular functions as transcription, translation, DNA replication/repair, and certain signaling pathways.

The key question regarding the U12-dependent spliceosome is on the biological significance of having two separate spliceosomes in the cells of higher eukaryotes. The U12-type introns are only rarely involved in alternative splicing as compared to the standard U2-type introns. Rather it seems that the role of the U12-dependent spliceosome is to regulate gene expression by adjusting the rate of intron excision as these introns are spliced more slowly than the normal U2-type introns. Thus our research is focused on the regulatory aspects of the U12-type spliceosome, but we are also studying mechanism of assembly and the architecture of this spliceosome.
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