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Surprising new mechanism for gene expression regulation

New research results reveal a function in gene expression regulation for a protein connected with the proper function of neurons. Further analysis of this unexpected function of protein binding may ultimately lead to the understanding of how neurological defects may result from abnormalities in this protein.

2012.06.08 | Lisbeth Heilesen

Manfred Schmid (left) and Torben Heick Jensen have revealed a function in gene expression regulation for a protein connected with the proper function of neurons. Further analysis of this unexpected function of protein binding may ultimately lead to the understanding of how neurological defects occur with abnormalities in this protein. Click figure for enlargement (Photo: Lisbeth Heilesen)

Figure: Poly(A) tails (a stretch of adenosine ‘A’ residues) are added at the end of the RNA (black line) by an enzyme called Pap1 (dark green oval symbol) and the tails are bound by the proteins Pab1 (light-green diamond symbol) and/or Nab2 (red circle symbol). In normal ‘wild-type’ cells (wt, left panel), the poly(A) tail is bound by Pab1, whereas Nab2-binding is prevented by Rrp6 (orange PacMan symbol). In addition, Rrp6 counteracts the action of the TRAMP complex (dark blue oval), which can extend tails beyond normal length. Both functions are revealed in mutant yeast cells lacking Rrp6 (rrp6?, right panel), where Nab2 does bind poly(A) tails and TRAMP extends poly(A) tails beyond their normal length (hyperadenylation). Click figure for enlargement (Figure: Manfred Schmid).

The researchers studied a protein called Nab2, which is found in baker’s yeast. Intriguingly, the human version of the Nab2 protein – called ZC3H14 – is required for the proper function of neurons. Mutations in the ZC3H14 gene were recently linked to the inherited disease NS-ARID, which causes intellectual disability in children. Studies from yeast may therefore shed light on the function of the human protein and ultimately on how alterations in gene expression can lead to neurological defects.

These results have just been published online in the prestigious American journal Molecular Cell. The work was a joint collaboration between researchers at Tufts University School of Medicine, Boston, the European Molecular Biology Laboratory, Heidelberg, and the Danish National Research Foundation’s Centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology and Genetics, Aarhus University.

Background

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. The number of proteins that need to be produced by individual cells varies greatly according to cell type and growth condition. Cells therefore maintain strict control over the gene expression process.

The present study discovered a new regulatory principle for controlling gene expression that targets the so-called messenger RNA (mRNA), which is a copy of the genomic information that serves as a template for protein synthesis. Control over the amount of mRNA is therefore a key to managing how much protein is produced in a cell and therefore a key to regulating cellular metabolism.

The mRNA is a long linear molecule that contains a specific tag at its rear end, the so-called poly(A) tail. This stretch of adenosine residues distinguishes mRNA from other types of cellular RNA and is specifically required to target mRNAs to protein-producing factories. Like their protein heirs, mRNAs are constantly produced and degraded, and the amount of mRNA present inside a cell is determined by the balance between its production and degradation rates.

The new results

In the new study, an unexpected function was disclosed of a protein binding to mRNA poly(A) tails in baker’s yeast. This protein, Nab2, was previously only believed to be required for the protection of mRNA poly(A) tails and the cellular transport of mRNA. However, the new research now shows that Nab2 also marks mRNA precursors for degradation provided they are retained in cell nuclei and therefore not amenable to protein synthesis.

Overall, this process is therefore – on the one hand – a new type of quality control measure that removes dysfunctional RNAs and – on the other hand – a mechanism that can be exploited by the cell for gene expression regulation purposes.

Future studies

Future efforts will now be devoted to exploring in detail which kinds of different cellular RNAs are amenable to regulation by Nab2. This may reveal secrets about Nab2’s famous human cousin ZC3H14, which could ultimately lead to an understanding of how neurological defects occur when this factor is mutated.

The research project was carried out by Senior Postdoctoral Fellow Manfred Schmid together with PhD students Mathias Bach Poulsen and Pawel Olszewski from Torben Heick Jensen’s laboratory at the Department of Molecular Biology and Genetics, Aarhus University, in a collaborative effort with scientists at Tufts University, Boston, USA, and the European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.


Further information

Professor Torben Heick Jensen
Director of the Centre for mRNP Biogenesis and Metabolism
Department of Molecular Biology and Genetics, Aarhus University, Denmark
thj@mb.au.dk
- +45 60202705 - www.mRNP.dk.

Text: Manfred Schmid and Lisbeth Heilesen

Public / media, Department of Molecular Biology and Genetics