Cellular Dumping Site Is Not Garbage After All

Learning how cells regulatethe newly discovered “mRNA cycle” may provide insights into how thecellular machinery runs amok in diseases like cancer.

Scientistshad previously thought the messenger molecules, known as mRNAs, weremanufactured, used, decommissioned and then sent on a one-way journeyto the garbage dump.

These cellular garbage dumps, calledP-bodies, turn out to be storage depots, not landfills. After use, mRNAmolecules are temporarily deactivated for storage purposes. The cellcan then either destroy the mRNA or recondition pre-used mRNA so it canbe put back into service if needed.

P-bodies are also involved in determining whether specific mRNAs are used to make proteins, a process called translation.

"Wewere surprised to find that the P-bodies were involved in regulatingtranslation," said research team leader Roy Parker, a Regents’Professor of molecular and cellular biology at The University ofArizona in Tucson and an Investigator with the Howard Hughes MedicalInstitute. In 2003, his lab was the first to name and describe afunction for P-bodies.

Parker said of the new finding, "Itsuggests P-bodies have a much broader role in controlling theactivities of the cell than we realized."

Parker and first authorJeff Coller report P-bodies' role in the control of translation in theSept. 23 issue of the journal Cell. Coller, who did the research whileat UA as a postdoctoral fellow with the Howard Hughes MedicalInstitute, is now an assistant professor in the Center for RNAMolecular Biology at Case Western Reserve University in Cleveland, Ohio.

TheParker lab's findings about P-bodies serving as storage depots wasreleased online Sept. 1, 2005 and will be published in an upcomingissue of Science. Complete citations for the two papers can be found atthe end of this release. The Howard Hughes Medical Institute and theNational Institutes of Health funded the research.

To live andgrow, cells convert the genetic instructions stored in DNA intoproteins. However, only some of the myriad instructions stored in genesare useful at any one time. Researchers want to figure out how cellsswitch from manufacturing one type of protein to another. mRNAmolecules are key in the manufacturing process because they carry theprotein-assembly instructions from the DNA to the assembly plant.

AlthoughP-bodies were initially identified as just garbage dumps for used mRNA,Parker and his colleagues suspected P-bodies played a more importantrole in determining which proteins a cell makes.

The researchersinvestigated whether two proteins known to decommission mRNA, Dhh1p andPat1p, were involved in regulating the translation of mRNA'sinstructions into proteins. The scientists did their experiments withcommon baker's yeast, a one-celled organism known to scientists asSaccharomyces cerevisiae.

To see what happened if the cellularmachinery didn't work right, the researchers compared the behavior ofmutant yeast cells to normal yeast cells.

Coller and Parkertested mutant cells that lacked one or both proteins to see how theycompared with normal cells. Under the microscope, only 10 percent ofthe mutant cells that lacked both proteins had P-bodies, whereas almostall the normal cells had P-bodies. In addition, the mutant cells couldno longer turn off the use of mRNAs under the appropriate conditions.Parker said, "Cells missing these proteins could no longer turn offmRNAs and could no longer make P-bodies."

The team thenengineered yeast cells to produce an overabundance of the proteins andrepeated the experiments with those cells. Those cells stopped growing.Parker said, "The mRNAs are all driven away from the assemblyfactories. When you look through the microscope, the cells have hugeP-bodies. It's very dramatic."

Overabundance of a human proteinsimilar to Dhh1p occurs in many tumors, but the function of the proteinis unknown, Parker said. In another experiment, the team put some mRNA,some protein-assembly plants and some of the human protein, referred toas RCK, into test tubes.

When RCK was added, mRNAs did not enterthe assembly plants, suggesting that the human protein prevents cellsfrom translating mRNA's instructions into the proteins that cells needto thrive. "Adding this protein would screw it up," Parker said. "Theprotein suppresses the translation process."

People initiallythought that switching from making one protein to another happenedsolely by blocking the assembly of the protein-making machinery. Collerand Parker's Cell paper shows that the regulation occurs by determiningwhether or not mRNA will enter the assembly plant or be shipped to astorage depot. Contrary to previous beliefs, the team suspects the cellcan bypass the assembly plant altogether and send unneeded mRNAsstraight to P-bodies to be degraded or eventually recycled.

Parker said his lab's next step is examining the potential role of P-bodies in memory and in viral infections.

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JeffColler and Roy Parker's paper, "General translational repression byactivators of mRNA decapping," will be published in the Sept. 23 issueof the journal Cell.

Muriel Brengues, Daniela Teixeira and RoyParker, all of The University of Arizona, are the authors of the paper,"Movement of eukaryotic mRNAs between polysomes and cytoplasmicprocessing bodies," that was published online in Science Express onSept. 1 at www.sciencexpress.org, DOI number: 10.1126/science.1115791.