Published online 30 May 2008 | Nature | doi:10.1038/news.2008.867

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Energy-hungry cells die if they can't put the brakes on protein production.

Keeping a lid on ribosome activity is key to cells avoiding runaway energy use. TIM EVANS/SPL

Researchers have found a protein complex that slows down a cell's protein-production machinery when energy is running low. The complex, called eNoSC, is critical for cell survival: energy-starved cells that do not have components of this complex rapidly self-destruct.

Proteins are constructed by complex molecular machines called ribosomes, which are made of RNA and protein. Mammals contain hundreds of copies of the genes that encode ribosomal RNA (rRNA) so that cells can crank out many ribosomes simultaneously. Ribosome production is one of the biggest energy investments a cell can make.

Over the years it has become clear that cells do not just blindly churn out ribosomes. “It is a major energy drain on the cell,” says molecular biologist Janet Stein of the University of Massachusetts Medical School in Worcester. “It’s definitely one of those things that a cell doesn’t want to be spending ATP on if it isn’t necessary.”

Instead, complex levels of regulation tweak ribosome production as energy needs fluctuate. Cells that are growing slowly produce less rRNA than those that are dividing rapidly. And cells taking on a new identity, to become a bone cell or a muscle cell, for instance, modify rRNA production to accommodate the requirements of the job1. “It’s such an important part of the cell that you can’t just have one way of regulating it,” says Stein.

Complex machinery

Previous work had shown that rRNA gene expression is in part regulated by chemical changes made to the proteins, called histones, that are associated with DNA. Now, Junn Yanagisawa of the University of Tsukuba in Japan and his colleagues have identified a complex of proteins that is responsible for these changes2.

The eNoSC complex contains three proteins, including the SIRT1 protein which is thought to play a part in helping a cell cope when nutrients run low. The complex reduces rRNA production in glucose-starved cells, providing a way to slow down protein production when energy is in short supply.

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Furthermore, the researchers found that glucose-hungry cells died more rapidly when production of any of the three proteins within eNoSC was inhibited. But the death rate of cells grown in medium containing plenty of glucose was unaffected by the loss of eNoSC.

The findings "bring us closer to understanding how calorie restriction or energy level comes to regulate ribosomal gene expression”, says Stein. But Yanagisawa’s work was done in cancer cells, which are easier to grow in culture and which have particularly high energy demands owing to their rapid proliferation. An important follow-up, says Stein would be to repeat the experiments in non-cancerous cells.

Yanigasawa says that he and his colleagues are now comparing the response of non-cancerous and cancerous cells to starvation. “Such studies could provide a basis for a new strategy of cancer therapy,” he says.

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