The Lamond group have been awarded a £1.128 million BBSRC research grant to support new studies that will dissect RNA processing mechanisms in the nuclei of human cells. These studies can help to explain molecular mechanisms involved in human diseases, including inherited disorders, cancer and viral infection and may identify new potential drug targets and protein biomarkers for future therapeutic applications.
The 3 year project, entitled “Molecular Analysis of Nuclear Bodies and RNP Trafficking Pathways in the Cell Nucleus”, builds upon a body of work undertaken by the Lamond group over a number of years. Some of this research was published in the Journal of Biological Chemistry in 2014 and eLife in 2017.
The newly funded project will use novel chemical probes to analyse the relation between the pre-mRNA and pre-rRNA processing machineries and the different types of subnuclear bodies. The structure and composition of nuclear bodies, such as nucleoli, Cajal bodies and splicing speckles, is dynamic and can vary in response to cell growth, environmental signals and disease mechanisms. Novel small molecule modulators, identified in a collaboration between the Lamond and Gray groups in SLS, were found to alter both the structure and composition of subnuclear bodies and inhibit specific RNA processing reactions.
This project will identify the protein targets of these ‘Nuclear Body Modulator’ (NBM) compounds and characterise their mechanism of action at both the biochemical and cellular levels. This includes a collaboration with Gareth Griffiths and colleagues (University of Oslo) to perform in depth ultrastructural analyses of human cell nuclei and how they are altered by the NBMs, using state of the art electron microscopy.