Department of Cell Biology


RNA machines and their roles in disease: ALS and cancer

Examples of ongoing projects include the following:

1. Role of RNA/DNA binding proteins in ALS pathogenesis

ALS is a fatal adult-onset motor neuron disease with no effective treatments.  Greater than one third of ALS-causative genes as well as multiple genes that cause the childhood motor neuron disease spinal muscular atrophy (SMA) encode RNA/DNA binding proteins with roles in gene expression. Consistent with this observation, we found that most of these ALS or SMA-causative proteins are present in the RNAPII/U1 snRNP gene expression machinery. Moreover, we found that two of the proteins in this machinery, the ALS protein FUS and the SMA protein SMN, interact directly. This observation provided the first evidence that ALS and SMA are linked at the molecular level, and we have now extended the molecular links between these two motor neuron diseases (see Chi et al, 2018 and other studies in publications link). In light of the molecular links between ALS and SMA and the extensive association of the ALS/SMA-causative proteins with the RNAPII/U1 snRNP machinery, a critical unanswered question is whether these proteins converge on a common downstream cellular pathway, and this is a key goal of our current research.

2. Role of the essential splicing factor SF3B1 in hematological cancer.

In early work, we purified the human spliceosome and cloned and characterized many of its components. Among these were the subunits of two U2 snRNP-associated complexes, known as SF3a and SF3b. Our characterization of SAP155 (now called SF3B1) revealed that it associates with pre-mRNA at the catalytic heart of the spliceosome, and the other SF3a/b subunits bind nearby. Subsequently, other researchers discovered that SF3B1 mutations underlie numerous cancers, with hematological cancers being by far the most frequently associated with SF3B1 mutation. One of our current goals is to understand why mutations in an essential splicing factor, found in every cell type in the body, leads to hematological cancers. To approach this problem, we CRISPR-edited the most common cancer causing SF3B1 mutation into human embryonic stem cells and are using RNA-seq to examine gene expression and splicing changes in these cells. Through these studies we hope to discover how SF3B1 mutation causes blood cancers as well as to identify therapeutic strategies for these diseases.