Award details

Nuclear RNA surveillance of genome expression: From yeast to mammals

Reference	BB/F010273/1
Principal Investigator / Supervisor	Professor Nicholas Proudfoot
Co-Investigators / Co-Supervisors
Institution	University of Oxford
Department	Sir William Dunn Sch of Pathology
Funding type	Research
Value (£)	256,982
Status	Completed
Type	Research Grant
Start date	01/09/2007
End date	31/05/2010
Duration	33 months

Abstract

This project will investigate the role and metabolism of excess non-coding transcripts generated by RNA polymerase II transcription of mammalian protein coding genes. These non coding transcripts derive from the extensive intronic regions of genes as well as sequences downstream of the poly(A) signal, but prior to transcriptional termination sites. We are focusing on novel transcript cleavage sites termed co-transcriptional cleavage (CoTC) elements. We originally found these sequences in termination regions of genes but will also look for their presence in introns. At the same time we will investigate the related role of co-transcriptional pre-microRNA maturation from introns. Once initial transcript cleavage occurs we will investigate the role of 5'->3' and 3'->5' exonucleases which following recruitment to RNA cleavage sites may promote rapid degradation of the non-coding RNA. This co-transcriptional RNA turn over process is involved in the maturation of functional mRNA but will also be critical for the degradation of incorrectly spliced or polyadenylated mRNAs. As such this process now referred to as nuclear RNA surveillance (NuRNASu provides a front line of protection in the cell from aberrant gene expression. Finally we will investigate the function of intergenic transcription that may be widespread in eukaryotic genomes. We will focus on this class of non-coding transcript that we originally discovered in the human beta globin gene locus. All of these experiments will use modern molecular biology and genetic approaches including RNA interference mediated mRNA knock-down technology, Chromatin analysis (ChIP and 3C), quantitative RT/PCR procedures, protein isolation and characterisation and RNA:protein interaction analyses.

Summary

The successful production of proteins from their gene blueprint (DNA) requires a key intermediate step in which a particular gene is selected by complex molecular machines and initially copied into a related RNA molecule called the transcript. However this process is far more complex than initially predicted as much of the RNA transcript does not directly encode protein and is referred to as non-coding RNA. Surprisingly gene transcripts are predominantly non-coding so that the protein coding portions must be joined together forming so called messenger RNA with the non-coding (intronic) RNA chopped out by a process called RNA splicing. Indeed splicing can occur in different ways so that many different messenger RNAs can be generated from just one initial RNA transcript. We have shown that non-coding RNA is first removed from the gene transcript before splicing occurs and at the same time that the transcript is being synthesised. Thus non-coding RNA can be sorted out and removed before critical splicing events take place. This seemingly wasteful mechanism is not only employed to help make the process of messenger RNA production more efficient and better regulated but is also used to completely degrade any messenger RNAs that might have protein coding defects. Removal of such mutant messenger RNAs is likely to be a critical quality control mechanism to prevent the synthesis of the wrong protein which in turn could have damaging effects on cell function. This mechanism is now given the name of Nuclear RNA Surveillance (NuRNASu). In the absence of this intricate quality control process cells will become deregulated leading to diseases such as cancer.

Committee	Closed Committee - Genes & Developmental Biology (GDB)
Research Topics	Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	EUROCORES RNA Quality (EURNAQ) [2007]
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/F010656/1 Nuclear RNA surveillance of genome expression: From yeast to mammals

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