UMMS RESEARCHERS IDENTIFY ESSENTIAL COMPONENT OF GENE SILENCING PATHWAY 

June 13, 2006 

WORCESTER, Mass -Proving the old adage that size doesn't matter, the smallest of genetic elements are drawing significant attention from the scientific community. In recent years, two classes of small RNAs, short interfering RNAs (siRNAs) and microRNAs (miRNAs), have become an exciting area of study with significant roles in a range of biological functions, most notably gene silencing. Nearly 15 years after the discovery of this mechanism to suppress gene expression, these tiny RNAs have hit the big time, drastically changing the way scientists think about DNA, RNA and how genes function. Now, researchers at the University of Massachusetts Medical School have made important strides in this area, identifying an essential component of the machinery required for miRNAs particular ability to suppress a gene's function.
 
MiRNA was largely unexamined a decade ago. However, as scientists have found that many miRNAs exist in the biological systems of plants, humans and animals, interest has surged in these tiny elements of the genome and their role in gene regulation. Contrary to the function of messenger RNA (mRNA) which translates instructions from genes to produce proteins, miRNA actually prevents the creation of proteins. In "Translation Repression in Human Cells by Micro RNA-induced Gene Silencing Requires RCK/p54,"published in an advanced online publication of the June 13 Public Library of Science Biology, Professor of Biochemistry and Molecular Pharmacology Tariq M. Rana and Graduate Student Chia-ying Chu, demonstrate that a particular human protein (RCK/p54) plays a key role in miRNA-mediated gene silencing.  Further, they demonstrate that the protein facilitates formation of special structures in the cell called P-bodies. While previously proposed to be necessary for miRNA gene silencing, Rana and Chu posit that P-bodies are actually the consequence of translation repression.
 

To create proteins, genes send messages in the form of mRNA molecules to the protein producing factories within cells. In the best known mechanism of gene silencing, RNA interference (RNAi), a message-matching process is used to stop those mRNA molecules from reaching their destinations. To do that, RNAi tools including siRNAs and proteins known as Dicer and those of the Argonaute family, contain a template with bits of information that correspond, one-for-one, with the information encoded on the messages sent by the genes. When the messages match up, the RNAi machinery destroys the messenger, thereby preventing protein production. 

Although RNAi has commonly been associated with siRNAs, this process is largely mediated in plants by miRNAs and examples of miRNA-mediated RNAi have been found in mammals and viruses. In addition, there is growing evidence that miRNAs are important in human disease, including cancers. Still, the mechanisms by which miRNAs inhibit the message are less understood than those of RNAi. When siRNAs pair only partially with their targets, they cannot direct the destruction of the messenger as in RNAi. In the instances where there is not perfect complementarity, miRNA comes into play to block translation of the mRNA into protein. Similar to siRNA, miRNAs are assembled into silencing complexes that contain Dicer, Argonaute proteins, and other cellular factors and target a specific-although not perfectly matched-region of the mRNA. The target mRNA is then sequestered into the P-bodies, distinct sites within the cytoplasm (that is, not in the nucleus), away from translational machinery. These sites, P-bodies, effectively serve as the sites for the accumulation of mRNAs that are destined for storage or degradation. 

To further understand the mechanism that governed this process, Rana and Chu sought to identify additional proteins involved in the sequestering of the mRNA. Previous research has demonstrated that certain members of the Argonaute family of proteins are essential to RNAi and were concentrated in the P-bodies. In this paper, Rana and Chu found that, through its direct interactions with the Argonaute proteins, RCK/p54 localizes to P bodies, and demonstrate that in its absence; the miRNA machinery falls apart, indicating that the protein is an essential component of miRNA-mediated repression. The paper's findings also assert that P-bodies are not essential for the miRNA repression process, but are in fact the consequence of the process. Further, far from being the site of mRNA degradation solely, these P-bodies are sites for the storage of mRNAs, which can then be degraded or activated as needed. 

"We are pleased that the study of RNAi has intensified research on miRNAs. As a naturally occurring phenomenon in organisms, miRNA-mediated gene silencing offers another powerful new tool for science," Rana explained. "Based upon our intriguing results, we look forward to investigating what determines the balance between active translation and repression of mRNA and how cells control that process." 

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The University of Massachusetts Medical School, one of the fastest growing academic health centers in the country, has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research.  The Medical School attracts more than $174 million in research funding annually, 80 percent of which comes from federal funding sources. UMMS is the academic partner of UMass Memorial Health Care, the largest health care provider in Central Massachusetts. For more information visit www.umassmed.edu .
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Contact:  Kelly Bishop
508-856-2000