Dr Andrii Gorelik - University of Oxford

Dr Andrii Gorelik - University of Oxford

Location: 
Online
Start Time: 
Thu, 21/10/2021 - 9:30am
End Time: 
Thu, 21/10/2021 - 10:30am

Special Lecture hosted by Associate Dr Catia Pierotti – ACRF Chemical Biology division

 

Dr Andrii Gorelik

University of Oxford, UK

 

Exploiting and targeting irreversible protein modifications

 

Join via TEAMS

Including Q&A session

 

Virtually every process in eukaryotic cells is governed by post-translational modifications (PTMs) of proteins. However, functional studies of many PTMs are limited by the lack of genetic and chemical tools. In the first part of my talk, I will discuss an unusual type of protein glycosylation called O-GlcNAcylation whose dysregulation may lead to oncogenic reprogramming, brain diseases, and diabetes. In cells, O-GlcNAc is rapidly hydrolysed from proteins complicating the study of its site-specific functions. To address this, we harnessed the serendipitous promiscuity of O-GlcNAc transferase towards cysteines to genetically encode a stable sulphur-linked O-GlcNAc analogue using CRISPR-Cas9. This approach now allows researchers to understand the biological consequences of site-specific O-GlcNAcylation in living systems. The second part of my talk will focus on protein N-myristoylation, an irreversible lipid modification that regulates membrane trafficking and interactions of more than 100 proteins. N-myristoyltransferase (NMT) has been proposed as a target in cancer, but a rationale for selectivity is lacking. In large-scale screens, we discovered that cancers with a deregulated transcription factor MYC are acutely sensitive to NMT inhibitors in vitro and in vivo. Mechanistically, this is mediated by post-transcriptional failure in mitochondrial respiratory complex I function concurrent with loss of myristoylation and degradation of a complex I assembly factor via the N-degron pathway. Our findings establish a new paradigm in which pharmacological targeting of a constitutive protein modification is synthetically lethal in MYC-deregulated cancers.

 

Andrii Gorelik completed a Wellcome Trust-funded PhD at the University of Dundee (UK) in 2018, working on protein O-GlcNAcylation with Professor Daan van Aalten. He then undertook postdoctoral research at the Francis Crick Institute and Imperial College London with Professor Ed Tate in the field of PTM chemical biology, targeting protein N-myristoylation in cancer. In October 2021 Andrii joined Dr Ivan Ahel’s group at the University of Oxford to pursue postdoctoral research on non-canonical protein ADP-ribosylation.

Twitter: @AndriiGorelik

 

All welcome!