Scheme: University Research Fellowship
Organisation: Newcastle University
Dates: Oct 2016-Sep 2017
Summary: This project summary is not available for publication.
Dates: Oct 2011-Sep 2016
Summary: Almost the entire eukaryotic genome generates protein-coding and non-coding RNA transcripts, which are important in all aspects of gene expression and regulated by a sophisticated network of ribonucleases. My laboratory is interested in metal-dependent endoribonucleases with PilT N-terminus (PIN) domains that play key roles in RNA metabolism.
One project uses the model organism budding yeast to analyse the role of a putative PIN domain endonuclease in the nonsense-mediated decay (NMD) messenger (m)RNA surveillance pathway, which degrades faulty mRNAs that could otherwise be translated into potentially toxic proteins. Defects in the NMD pathway are linked to ~30% of all inherited human diseases (e.g. Duchenne muscular dystrophy, ß-thalassemia) and some types of cancer.
We are also interested in PIN domain endonucleases involved in RNA maturation, a process which often requires multiple processing steps. The assembly of ribosomes, large RNA-protein (RNP) machineries that synthesise all cellular proteins, is by far the most complex example. Ribosome biogenesis determines the proliferative rate of cells and defects are linked to human diseases (“ribosomopathies”) and cancer. Key events in ribosomal RNA processing are endonucleolytic cleavages that release mature rRNAs from a large precursor transcript, but many enzymes are not known. The presence of two PIN domain proteins in a large pre-rRNA processing complex is required for early cleavage events in eukaryotic ribosome biogenesis, but it is currently unclear if these proteins harbour enzymatic activity. Using a combination of in vitro and in vivo approaches, we analyse their function in budding yeast and human cells.
Studying fundamental, evolutionarily conserved processes such as RNA quality control and ribosome biogenesis in two eukaryotic systems offers a strong basis to clarify underlying mechanisms of genetic diseases, cancer and ageing, and will hence undoubtedly lead to the identification of therapeutic targ