Aaron Hoskins, PhD

From gene expression to cell division to moving a cell from here to there, biological life has evolved to depend on macromolecular machines made of many biomolecules working together to fulfill specific functions.  Our lab seeks to understand how these machines assemble from their individual components in vitro and in vivo.  We primarily study the eukaryotic spliceosome—a highly conserved machine composed of 5 snRNAs and about 100 proteins found everywhere from S. cerevisiae to H. sapiens.  The spliceosome is responsible for removing introns from precursor mRNA transcripts to generate mature mRNAs.  A single pre-mRNA has the potential to generate many different mRNAs by alternative splicing, which is a central mechanism for encoding genomic complexity in metazoans.  We are interested in how the early steps in spliceosome assembly are regulated, how ATP hydrolysis facilitates these steps, and how spliceosomes and their component small nuclear ribonucleoproteins (snRNPs) are correctly assembled and in the proper location.  These steps are important for understanding basic human biology and how splicing and snRNP assembly can be misregulated in diseases such as cancer, retinitis pigmentosa, or spinal muscular atrophy.

To understand these assembly reactions, we use a combination of chemical, genetic, and physical tools.  With hundreds of billions of molecules all doing different things, these complex assembly pathways are often too convoluted to study using traditional approaches; so, we use single molecule fluorescence microscopy to study these assembly reactions one molecule at a time.  Single molecule approaches greatly facilitate uncovering assembly pathways of these machines in real time.  We complement these single molecule experiments with a number of other biochemical, genetic, and microscopic assays both in the test tube and in the cell to provide a clearer picture of how cellular machines are built from dozens or even hundreds of subunits.