A “molecular torpedo” improves gene quality
Media releaseNew research reveals a molecular mechanism that improves gene expression and thereby cell survival.
Scientists from Aarhus University have discovered a new "molecular torpedo" mechanism that discards toxic genetic information floating around inside our cells. The discovery adds to a growing list of sophisticated ways in which cells can protect themselves by "cleaning up" the results of sloppy gene expression that - if left unattended - would otherwise contaminate the cell interior and disturb normal growth and development. A detailed understanding of such quality control systems therefore not only serves to delineate basic principles underlying human gene expression programmes, but also facilitates the planning of future strategies for drug development and medical intervention.
The work that has just been published in the prestigious journal Molecular Cell by scientists from the Danish National Research Foundation's "Centre for mRNP Biogenesis and Metabolism" at the Department of Molecular Biology, Aarhus University, was spearheaded by Postdoc Silvia Jimeno González with the help of Postdoc Francisco Malagón and Research Assistant Line Linegaard Haaning under the supervision of Centre Director Torben Heick Jensen.
Background
The term "gene expression" refers to the production of proteins based on the genetic information stored in the cellular DNA (the genome). In higher organisms such as humans, where DNA is placed in the cell nucleus and protein production occurs in the cytoplasm, messenger RNA (mRNA) molecules are required for the transfer of genetic information.
However, this cellular journey is hazardous and, in order to survive, mRNAs go through several preparative steps of enzymatic modifications and packaging with proteins into so-called mRNA protein particles (mRNPs). If these steps are not executed properly, the mRNA is destroyed by cellular quality control machineries. This concept is a central aspect of mRNP formation and it guarantees the accuracy of gene expression. If the gene expression does not function properly, this can lead to numerous diseases.
The scientists have now found a new quality control mechanism that is triggered when an error occurs in the process.
A quality control mechanism at the first step of mRNA processing
The first step in gene expression is the "transcription" of DNA into an mRNA copy by the RNA polymerase II (RNAPII) enzyme. Here a so-called "cap" structure is added to the front end of the mRNA. This structure is absolutely vital for the protection and functionality of the mRNA, and the scientists from Aarhus have revealed a quality control mechanism that intervenes when the cap is not added. In this case an RNA degradation enzyme targets the "cap-less" RNA, and it chases after the RNAPII molecule like a torpedo, causing the defective RNA to terminate the process (see figure below). This torpedo mechanism thus serves to both degrade the malformed molecule and block the machinery producing it. As a consequence, the same RNAPII enzyme is given the chance to start transcription again to produce a successful product.
Although this work was performed with yeast as a model organism, all implicated proteins are also present in human cells. Thus, a similar quality control mechanism is likely to exist in higher organisms. Examining the underlying mechanisms governing cellular quality control is essential for our understanding of how cells tackle errors arising in gene expression and, during the course of time, may well aid in the development of medicine targeting such disease states.
Figure. An RNA degradation enzyme targets the "cap-less" RNA, and it chases after the RNAPII molecule like a torpedo, causing the defective RNA to terminate the process.
Under normal conditions (upper panel), the addition of the cap structure to the nascent RNA takes place shortly after transcription initiation. This process depends on the phosphorylation status of RNAPII that promotes the recruitment and activation of the capping enzymes (Ceg1p, Cet1p and Abd1p). If a problem arises in connection with capping (lower panel), the 5'-3' exonuclease Rat1p (and its co-factor Rai1p) degrades the nascent RNA and promotes transcription termination of RNAPII.
Figure in high resolution (300 dpi)
Link to the article published in Molecular Cell:
The yeast 5'-3' exonuclease Rat1p functions during transcription elongation by RNA polymerase II. Silvia Jimeno Gonzalez, Line Linegaard Haaning, Francisco Malagón, Torben Heick Jensen.
More information
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Professor Torben Heick Jensen Director of the Centre for mRNP Biogenesis and Metabolism |
26 February 2010
Lisbeth Heilesen (lh@mb.au.dk) - +45 8942 5075
Director of Communications, MA
Department of Molecular Biology
Aarhus University