Ryan D. Mohan
Biography
Professor Mohan is originally from Canada, where he earned his PhD at the Western University School of Physiology. His PhD thesis is entitled "Regulation of DNA damage processing by covalent modification of Thymine DNA glycosylase." In this work he discovered how post-translational modifications control function of proteins at the interface between gene regulation and DNA repair. These studies have implications for regulation of cytosine methylation, carcinogenesis, and for regulation of stem cell identity.
In mammals, CREB Binding Protein (CBP) and Thymine DNA Glycosylase (TDG) work together to coordinate cellular regulation of chromatin modification, DNA repair, and transcriptional activation. CBP and other proteins place novel post-translational modifications on Thymine DNA Glycosylase (TDG). These modifications were sometimes near each other, so he dissected the interplay between these modifications and their effect on TDG enzymatic function, conformation, subcellular localization, and protein-protein interactions using biochemistry, cell biology, in vivo/In vitro analysis.
His ongoing work leverages naturally occurring disease-causing mutations as models to reveal molecular functions of protein complexes important for human health. For example, polyglutamine expansion of Atxn7 causes the devastating disease spinocerebellar ataxia type 7 (SCA7), which leads to progressive blindness and nervous system degeneration in humans and in model organisms. Although Atxn7 is known to be a subunit of the Spt-Ada-Gcn5 Aceyltransferase (SAGA) chromatin remodeling complex, changes in gene expression are not able to explain phenotypes of this fatal disease.
Hypothesizing SAGA has unknown functions, he applied biochemistry, genetics, proteomics, cell biology, microscopy, and in vitro/in vivo approaches to discover the full regulatory capabilities of SAGA. Once discovered, these novel functions were specifically altered to determine whether imbalances of them lead to nervous system degeneration or blindness. The studies below reveal the dynamic nature of the SAGA complex and demonstrate gene regulatory complexes have unexpected functions which may explain why analysis of gene expression provides an incomplete picture of why mutation of these complexes leads to disease.
Believing that Drosophila provides experimental advantages for revealing new functions, he began by discovering the Drosophila orthologue of Atxn7 and showed it functioned exclusively as a member of SAGA. There, the portion of Atxn7 subject to polyglutamine expansion anchors a deubiquitinase module to SAGA. Subsequently, he showed the deubiquitinase can be released by SAGA to act on substrates at a distance. Evidence suggested it was this regulation that might be misregulated to cause SCA7. He collaborated with another group to show these findings predicted sophisticated deubiquitinase regulation in mammals. Then, he discovered a major function of the deubiquitinase was to regulate the WAVE regulatory complex, which is a major regulator of the actin cytoskeleton. This work was the first to reveal a nuclear WAVE complex and establish a direct link between actin cytoskeleton regulators and gene expression regulators. He went on to show non-stop is a critical cell identity supervisor in the gut. There, non-stop is a subunit of the non-stop identity complex (NIC).
He is now pursuing a similar research strategy to discover new regulators of cell identity and move this work into the nervous system in order to perform comparative analysis. This body of work continues to provide new insight into co-regulation of gene expression and maintenance of cell identity. Importantly, the skills used to create this body of knowledge are flexible enough to apply them to any set of protein complexes which justify interrogation.
Training
Postdoctoral Training, Jerry L. Workman Laboratory, Stowers Institute, Kansas City, MO
Education
PhD, Western University, Canada
Areas of Expertise
Neurodegeneration, DNA repair, cytoskeleton, cell identity, protein complexes, mass spectrometry, aging, chromatin, post-translational modification, circadian rhythm, cancer.
Areas of Interest
Virology, exosomes.
Awards and Honors
Best Mentor, 2018, 2020
Grants
Mechanism and effects of communication between actin and gene regulatory complexes, National Institutes for Neurological Disease and Stroke (NINDS), R01NS117539, 2021/06-2026/06.