1). Mechanistically characterise reverse transcriptase-based phage defence systems
2). Discovery of new RNA-based systems using genomics
3. The mechanisms of R2 retrotransposon mobility
Genetic information typically flows in one direction: from DNA to RNA to protein. We are fascinated by reverse transcription, where this flow is flipped on its head and RNA is rewritten to DNA. Reverse transcriptases are famously used by retroviruses like HIV to invade genomes, but it turns out they are used by more than just genomic parasites.
We explore the frontiers of RNA biology by discovering new functions for reverse transcription. We already recognise that fundamental phenomena in molecular biology like splicing and telomere extension evolved from this ancient process, and we want to know: What else is out there? Using a combination of biochemistry, microbiology, and structural biology, we aim to discover new biological functions and harness them for applications in genomic medicine.
For example, bacteria are under constant threat of infection by viruses (called phages). We've found that many bacteria are armed with sophisticated viral defence systems powered by reverse transcription. While the mechanisms of these defences are largely mysterious, we recently discovered how one such system works. We found that upon phage infection, a bacterial reverse transcriptase synthesises a toxic repetitive gene from an RNA template. The single infected cell stops growing and thereby saves the entire bacterial population from the virus.
We are now investigating the mechanisms of other reverse transcriptase-based defence systems, to uncover what we expect to be a remarkable diversity of mechanisms that showcase the creativity of evolution.
Biography
Max Wilkinson is an Assistant Member in the Structural Biology Program at Sloan Kettering. He received his PhD from the University of Cambridge, where he worked at the MRC Laboratory of Molecular Biology with Dr. Kiyoshi Nagai on cryo-EM structures of the spliceosome. As a Helen Hay Whitney Fellow in Prof. Feng Zhang's lab at the Broad Institute, he worked on retrotransposon structural biology and discovering mechanisms of phage defence systems. He was awarded the Scaringe Award by the RNA Society in 2019.
