Stewart Shuman

To understand the mechanisms and structures of enzymes that perform and regulate DNA and RNA transactions, we integrate diverse experimental approaches – including microbiology, biochemistry, structural biology, and genetics - and apply them to model systems ranging from viruses to bacteria to fungi to mammalian cells. We are interested in the evolution of enzyme systems and pathways and the ancestral connections between RNA and DNA metabolism. An explicit aim is to identify novel enzymatic targets for treatment of human diseases, especially infectious diseases. Our research efforts have been fruitful, i.e., discovery of new enzymes, new pathways, new protein structures, and distinctive enzyme specificities and chemistries.

Key themes are: (i) the structure, mechanism, and distinctive specificities of fungal tRNA splicing enzymes Trl1 and Tpt1 – as paradigms of an RNA repair system essential for normal cell physiology and as promising targets for anti-fungal drug discovery; (ii) the unique catalytic mechanism, end-specificity, and regulation of GTP-dependent 3'-PO4/5'-OH RNA ligase RtcB, which catalyzes tRNA splicing in animals and RNA repair in bacteria; (iii) biochemical and structural characterization of novel regulators of RNA 3'-processing/transcription termination in fission yeast (collaboration with Beate Schwer at Weill Cornell); (iv) defining the cellular responses and adaptations (at the level of the transcriptome, the proteome, and the metabolome) to chronic phosphate limitation; (v) mechanisms of DNA recombination, repair, and mutagenesis in mycobacteria, a genus that includes the human pathogen M. tuberculosis (collaboration with Michael Glickman at MSKCC).