New method uncovers the importance of keeping a good nuclear RNA hygiene
How cells translate their genetic information into functional RNA and protein is a central question in biology. Researchers from the Department of Molecular Biology and Genetics at Aarhus University have invented a new technology to study regulatory principles of gene expression. Applying this methodology to bakers yeast they found that RNAs that fail to get exported from their site of synthesis in the cell nucleus are rapidly decayed. This provides a new regulatory principle in the complex process of gene expression.
All living cells are small factories that constantly produce new proteins and recycle old ones. Information about the nature and the amount of proteins produced is encoded in a cell’s genome and decoded into proteins in a complex chain of events termed “gene expression”. This process varies greatly between cell types and growth conditions and therefore determines the identity of individual cells. Strict control over the gene expression process is therefore of paramount importance for all life.
In two studies, the researchers have now discovered a new aspect of gene expression that targets the so-called messenger RNA (mRNA). mRNAs are copies of individual genes that carry the genetic information from the genome, residing in the cell nucleus, to the site of protein synthesis in the cytoplasm. The transport of mRNA from the nucleus to the cytoplasm is therefore a central step in gene expression.
The new research investigated the cellular role of a protein called Mex67, which transports mRNA from the nucleus to the cytoplasm. Unexpectedly, depletion of Mex67 from cell nuclei caused not only the expected complete block of mRNA nuclear export, but also a dramatic decline in cellular mRNA production. The same phenotype was observed upon depletion of other mRNA export factors and thus represent a general phenomenon. At this point, however, it was not clear whether the observed decline in mRNA production was due to a defect in transcribing new mRNA from the genomic template, or, due to rapid degradation of newly transcribed RNA.
To distinguish these possibilities, a method was established to simultaneously measure transcription, RNA levels and RNA decay from the same cell samples. Using this new tool, it could be determined that the defect observed in export-blocked cells derived from an untimely rapid mRNA decay in the nucleus. These results are in line with previous findings that mRNA is labile in cell nuclei and requires tight protection from dedicated proteins to fend off nuclear RNA decay factors. Under conditions of debilitated export, such protective factors become limiting, leaving newly synthesized mRNA prey to decay. Earlier research identified the protein Nab2, which binds the susceptible RNA rear end (the so-called 3’end), as an important protective factor. Consistently, the present studies found that Nab2 is also a critical determinant during export block. Here, the protein is sequestered and therefore in short supply, explaining the observed rapid mRNA decay phenotype (see Figure).
The uncovered decay of export-defective mRNA provides a new principle, termed “nuclear hygiene”, which allows cells to prevent the unnatural accumulation of mRNA in their nuclei to avoid that they interfere with normal cellular function. In addition, the work suggests that control of the balance between nuclear mRNA decay and export may be exploited by cells as a means to regulate gene expression.
The two projects, which have just been published online in Cell Reports, were carried out by team leader Manfred Schmid together with PostDoc Agnieszka Tudek from Torben Heick Jensen’s lab at the Department of Molecular Biology and Genetics, Aarhus University in a collaborative effort with scientists from the University of Edinburgh, UK.
- 'A nuclear export-block results in the decay of newly made polyadenylated RNAs' by Agnieszka Tudek, Manfred Schmid, Marius Makaras, J. David Barrass, Jean D. Beggs and Torben Heick Jensen
- 'Simultaneous Measurement of Transcriptional and Post-transcriptional Parameters by 3’end RNA-seq' by Manfred Schmid, Agnieszka Tudek, Torben Heick Jensen.