Cooperative Interactions Between the UPF Proteins and Nucleic Acids

Nonsense mediated mRNA decay (NMD) is a conserved eukaryotic surveillance mechanism that recognises and degrades mRNA transcripts containing premature termination codons. NMD prevents the formation of truncated proteins that could be detrimental to the cell and regulates ~10% of endogenous transcripts. Mutations in NMD factors are associated with neurodevelopmental disorders such as schizophrenia and autism. Despite the discovery of NMD 40 years ago, many questions regarding the molecular mechanisms of NMD including interactions between NMD factors remain unanswered. The three Up-frameshift (UPF) proteins UPF1, UPF2 and paralogs UPF3A and UPF3B play central roles in NMD through their interactions with the ribosome, each other and downstream NMD factors.

This project focuses on the characterisation of interactions between UPF factors, and with nucleic acids, with particular a focus on UPF2 and UPF3B. UPF2 and UPF3B are conserved from yeast to men, poorly characterised and their role in NMD is largely unknown. Biochemical and biophysical assays, coupled with structural characterisation by crystallography, electron microscopy and computational predictions using AlphaFold and Rosetta will be performed to shed light on the roles of UPF2 and UPF3B in NMD.