MicroRNA processing: Testing structural biology hypotheses in primary human cells

Overview

A fundamental challenge in biomedical research is to understand the relationship between the structure of individual biomolecules and their function in health and disease. The aim of this project is to generate an interdisciplinary platform that will facilitate the functional correlation of structural information determined in a test-tube with biological activity occurring in a human cell.

The project will focus on TRBP, a protein with a fundamental role in development of chronic diseases, such as cancer and chronic inflammation. TRBP is an essential component of a cellular machine that processes a unique class of regulatory molecules called microRNAs. This microRNA-processing machinery is essential for mammalian development. Previous studies have characterised the structural and functional features of TRBP and its interaction with other proteins and RNA. This project combines these distinct but highly complementary approaches to enhance our understanding of the biology of the microRNA processing machinery and is intended as a springboard for future studies in microRNA biogenesis.

In detail

A fundamental challenge in biomedical research is to understand the relationship between the structure of individual biomolecules and their function in health and disease. The aim of this project is to generate an interdisciplinary platform that will facilitate the functional correlation of structural information determined in a test-tube with biological activity occurring in a human cell.

The project will focus on TRBP, a protein with a fundamental role in development of chronic diseases, such as cancer and chronic inflammation. TRBP is an essential component of a cellular machine that processes a unique class of regulatory molecules called microRNAs. This microRNA-processing machinery is essential for mammalian development. Previous studies have characterised the structural and functional features of TRBP and its interaction with other proteins and RNA. Here, it is proposed to combine these distinct but highly complementary approaches to enhance our understanding of the biology of the microRNA processing machinery. It is intended that this project will provide a springboard for future studies in microRNA biogenesis.

The experimental part of the study has provided intriguing results with regards to the structure and function of TRBP. Dimitris Lagos was invited to give a talk on parts of this work at the Keystone RNA Silencing meeting (Seattle, February 2014), the most prestigious symposium on RNA silencing.

This project has initiated a collaboration between the Lagos (RNA biology) and Plevin (Structural Biology) Groups. This also led to attracting a CIDCATS-funded PhD student (Alex Heyam - 2012 cohort) to work on the project. This work also provided the platform for a wider collaboration network including colleagues from Chemistry and YSBL. The project outcomes will also directly feed into a second PhD project (starting Oct 2014), which is funded as part of a White Rose doctoral train programme on RNA/ligand interactions.

Outputs

Grants

• Norman Maitland, Yorkshire Cancer Research, Can we exploit microRNA expression patterns to improve the prognosis for prostate cancer patients?, £170,348
• Michael Plevin, BBSRC, White Rose Doctoral Training Programme 'Structural and Mechanistic Biology at the RNA/Ligand Interface', £271,512