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Host genes under the knife

A Danish research team has analysed the use of a particular cellular RNA degradation mechanism, which has revealed how the expression of the most complex class of genes in human cells is controlled. The study contributes to an understanding of the cell’s basic regulatory tools, and the results may eventually lead to a better understanding of the molecular background for certain forms of cancer.

2014.11.18 | Lisbeth Heilesen

The research team from Aarhus University behind the new results (left: Professor Torben Heick-Jensen, Senior Researcher Søren Lykke-Andersen and PhD student Britt Ardal). Photo: Lisbeth Heilesen

Organised and adaptable gene expression is a prerequisite for all life. Most genes – regardless of whether they are protein-coding or RNA-coding – are initially transcribed to an ‘immature’ RNA molecule that is processed in different ways, whereby the ‘mature’ RNA is produced. The balance between synthesis, processing and degradation determines the number of functional RNA copies found in a cell at any given time.

The thousands of human genes are built up in different ways, but protein-coding genes typically consist of a number of exons interrupted by introns. Following transcription, the mature protein-coding messenger RNA (mRNA) molecule is processed by introns being cut out of the primary transcript and exons being joined together in a process called splicing – the excised introns are normally degraded rapidly.

Particularly complex genes known as host genes have exons that code for mRNA, but one or more of their introns code(s) for small functional RNA molecules. A particular group of such small RNA molecules – small nucleolar RNAs (snoRNAs) – is essential for the processing of functional ribosomal RNA (rRNA) molecules, which constitute up to 95% of a cell’s total RNA mass and are the cornerstone of the ribosomes – the cell’s protein synthesis machinery. The formation of mature snoRNA molecules from introns can only take place if the snoRNA-containing intron is cut out of the primary transcript in the splicing process.

The starting point for the current studies was a next-generation sequencing method that was designed to identify substrates and degradation intermediates from a cellular mRNA degradation pathway called nonsense-mediated mRNA decay (NMD). The researchers were thereby able to describe new details about the basic molecular mechanism underlying NMD. One of their findings was that NMD primarily uses a molecular knife (an endonuclease) to cut its substrates into two pieces that are subsequently degraded rapidly by the cell’s general RNA degradation enzymes.

The results also showed that snoRNA host genes produce a remarkably large number of NMD substrates compared with other protein-coding genes, which underlines the fact that spliced mRNAs produced from snoRNA host genes can be regarded as by-products of snoRNA production.

Further studies showed that snoRNA host genes generally produce large amounts of transcripts, which results in the formation of corresponding amounts of snoRNA. For some host genes, this massive snoRNA production is accompanied by a matching expression of protein-coding mRNA, while the mRNA level in most cases is partly or wholly scaled down by means of NMD.

The results also indicate that host genes that code for more than one snoRNA often form alternative splicing variants that potentially enable differential expression of the individual snoRNAs. Because mRNA and snoRNA from snoRNA host genes are dysregulated in a number cancer types, it is natural to investigate whether this can be explained on the basis of the described results.

The results have just been published in the international journal Genes & Development, and were achieved via collaboration between researchers at the Danish National Research Foundation’s Centre for mRNP Biogenesis and Metabolism, Aarhus University, and the Bioinformatics Centre, University of Copenhagen.

Read the scientific article in Genes & Development: “Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes”.

The article is also described in the Perspectives section of the samme issue of Genes & Development: “Nonsense-mediated RNA decay: at the cutting edge of regulated snoRNA production”. Link will follow.

Further information

Centre Director Torben Heick Jensen
+45 6020 2705; thj@mbg.au.dk

or Senior Researcher Søren Lykke-Andersen

both at the Danish National Research Foundation’s Centre for mRNP Biogenesis and Metabolism,
Department of Molecular Biology and Genetics
Aarhus University, Denmark