Splicing of mRNA precursors is a nearly ubiquitous process in gene expression. Furthermore, over 95% of human genes encode transcripts that can be alternatively spliced to generate distinct isoforms, a process that is highly regulated during cell growth and differentiation. Not surprisingly, errors in splicing contribute to numerous human diseases, notably multiple different cancers. Such errors can arise in three separate ways, first by cis-acting mutations in cancer-associated genes, most frequently tumor suppressors, that lead to their mis-splicing; second by altered expression of regulatory proteins that control alternative splicing, and hence expression, of genes involved in growth control; and finally by mutations in genes that encode proteins that function in splicing or its regulation. In recent years, attention has focused more on splicing factor mutations.
The importance of splicing factor (SF) mutations in cancer was highlighted by Ogawa and colleagues in 2011, who identified mutations in a number of genes encoding SFs in Myelodysplastic Syndromes (MDS). Subsequent studies have shown that several of these genes are associated with other hematological malignancies as well as solid tumors. Perhaps most notable among these genes is SF3B1, which is the most commonly mutated gene in certain types of MDS and certain other malignancies, and the most frequently mutated SF gene in cancer. This was somewhat surprising, as SF3B1 is a core SF associated with U2 snRNP and is required for splicing of all of the >200,00 introns in the human transcriptome, although only several hundred are affected by SF3B1 mutations, which are all heterozygous base changes that exert neo-morphic effects on splicing. Here I will describe studies that are aimed at elucidating the molecular mechanism by which SF3B1 hot spot mutations affect splicing, as well as uncovering pathways dysregulated by splicing errors that lead to disease.