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How to target the RNA decay machinery

In collaboration with two other European groups, researchers from Aarhus University have uncovered molecular details leading to targetting of the major RNA decay machinery, the RNA exosome, to its nuclear RNA substrates. Studies can now be designed to address the role of this early nuclear RNA decay pathway in processes where rapid RNA decay may be critical, i.e. during embryonic development, cell differentiation and various stress conditions.

2015.01.08 | Lisbeth Heilesen

The co-occurrence of the NEXT complex and an accessible RNA 3’end drives an early RNA exosome decay. The NEXT complex, via its RNA-binding component RBM7, physically contacts RNAs early during their cellular lifecycle (1). NEXT binding does not automatically lead to decay by the exosome (2a), but the presence of NEXT provides the possibility for exosomal degradation, which can only occur upon emergence of an unprotected RNA 3’end (2b). One group of newly discovered NEXT substrates are metabolites of intronic snoRNA production events (3).

Nuclear RNA turnover

In the cell nucleus, the activity of the RNA exosome - the major nuclear 3’-5’ exoribonuclease - rules. Therefore, nuclear RNAs are usually well protected by proteins in order to fend off their untimely decay. On the other hand, this means that a set of exosome adaptors is needed to provide specificity, so that only unwanted molecules are removed. Such mode of RNA exosome targetting is well described in our ancestors – yeast, begging the question of how well this system is preserved through evolution to human cells.

The NEXT complex and its many substrates

Back in 2011, Michal Lubas, postdoc in the group of Torben Heick Jensen, discovered with his co-workers the so-called Nuclear EXosome Targeting (NEXT) complex as an activator of the nuclear exosome in human cells. The trimeric NEXT complex harbours the RNA helicase hMTR4, the zinc knuckle protein ZCCHC8 and the RNA-binding protein RBM7. More recent studies from the group showed that the NEXT/exosome axis serves to suppress pervasive activity of the human genome. Using this as a starting point, the Aarhus researchers aimed at delineating how molecular recognition of RNAs by NEXT takes place and how this leads to RNA degradation.

Detecting NEXT-RNA association transcriptome-wide

Using a transcriptome-wide in vivo RNA interaction approach, so-called iCLIP technology, coupled to massive parallel RNA sequencing, the present analysis discloses a large subset of NEXT-bound RNAs and reveals that NEXT physically contacts these RNAs early during their cellular lifecycle. In line with its early role in exosome activation, many NEXT-bound RNAs are short-lived species, like enhancer RNAs (eRNAs), PROMoter uPstream Transcripts  (PROMPTs), long noncoding RNAs (lncRNAs) and metabolites of small nucleolar/nuclear sn(o)RNAs production events. Interestingly, however, NEXT binding per se does not automatically lead to decay by the exosome. Instead the presence of NEXT merely ‘offers’ the possibility for exosomal degradation, which will only occur upon emergence of an unprotected RNA 3’end. This mode of NEXT action appears to provide a simple and efficient way of executing nuclear RNA quality control without a prior, and complicated, sorting mechanism.

The work, which is newly published in the open access journal Cell Reports (link), was conducted by postdoctoral researchers Michal Lubas and Peter Refsing Andersen from Torben Heick Jensen’s group at the Danish National Research Foundation-funded Centre for mRNP Biogenesis and Metabolism, Department Molecular Biology and Genetics, Aarhus University. The project was a collaboration with the groups of Grzegorz Kudla at the University of Edinburgh and Andrzej Dziembowski at the University of Warsaw.

Link to the scientific article in Cell Reports.

More information

Professor Torben Heick Jensen
Centre for mRNP Biogenesis and Metabolism
Department of Molecular Biology and Genetics
Aarhus University, Denmark
+45 6020 2705, thj@mbg.au.dk