Ross Smith

Biography

 I undertook my PhD in Physical Chemistry at the University of Canterbury in New Zealand. This was followed by about three years studying biological membranes at Duke University in North Carolina and a year and a half in the Institute Jozef Stefan in Ljubljana, Slovenia. My mentor at Duke was Charles Tanford, a very well known protein scientist and author (“The Physical Chemistry of Macromolecules”, “Proteins: the workhorses of cells” etc) who deduced the structure of antibody molecules before switching his attention to biomembranes (“The hydrophobic effect”). I subsequently held lectureships at the University of Sydney and La Trobe University before moving to Brisbane in 1983. I have spent sabbatical leave at McGill (Montreal), Oxford and Connecticut universities and the Scripps Research Institute (La Jolla, California).

Research Interest

 We are interested in RNA-binding proteins and their roles in development and disease. Most of our research centres on the heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 family of proteins. RNA trafficking in the cytoplasm Our initial experiments focussed on the molecular mechanism of trafficking of mRNAs in the cytoplasm of oligodendrocytes. In a series of papers, we described the protein (trans-acting factor) responsible for RNA trafficking and defined the minimum required cis-acting RNA element or motif (the A2RE). The same cis/trans pair of molecules was found in 2003 (Shan et al., J. Neurosci.) to transport A2RE-containing mRNAs to dendritic spines. This is still one of the best understood cytoplasmic mRNA transport pathways and is very important because the hnRNPs that are associated with trafficking granules appear to also be involved in memory formation and maintenance.  hnRNP A/B proteins in cancer RNA trafficking is just one of the roles for the multi-tasking hnRNP A2/B1 proteins. They also participate in packaging of nascent RNA, the regulation of alternative splicing of RNA, and in maintenance of telomeres. We have shown that hnRNPs A2 and A3 recognize the ssDNA repeat in the G-rich strand of mammalian telomeres (binding it at the A2RE site) and the RNA template of telomerase, the enzyme which maintains the length of telomeres, Increasing telomerase activity and thus telomere length favours cell survival. Over-expression of certain of the hnRNP A2/B1 proteins enhances cell proliferation and cancer. One hnRNP A2/B1 isoform, B1 is upregulated in several cancers, including non-small-cell lung cancer. On the contrary, we have also used shRNA to examine the effects of suppression of hnRNP expression in mammalian cells and in Zebrafish (using morpholinos).  Structure/function relationships We are using NMR spectroscopy and X-ray crystallography to determine the 3D structure of hnRNP A2 and its complexes with A2RE, the ssDNA telomere repeat and the A2-binding element of telomerase RNA. In summary, the hnRNPs regulate many of the normal pathways in which RNA participates (e.g. RNA packaging and splicing, memory formation, telomere maintenance) and, not surprisingly, they are key players in many diseases (e.g. cancer, Alzheimer’s Disease, ALS).