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New insights provide promise for development of tools to protect damaged tissues
Date:9/13/2010

wn of p53 inside such cells. But in 2005, Kastan and his colleagues showed that affected cells also produce more of the protein. Researchers reported that after DNA damage, a protein called RPL26 binds to a molecule called p53 messenger RNA, leading to a dramatic rise in p53 protein. Messenger RNA (mRNA) is part of the cell's protein production machinery that translates the genetic instructions inside cells into needed proteins.

Efforts to better understand how RPL26 functioned led investigators to this latest discovery. Researchers showed that optimal p53 production required RPL26 to bind to a structure in mRNA not previously seen in mammalian cells.

The structure forms when the ends of the normally single-stranded mRNA molecule come together and make a short region of double-stranded RNA. Those ends must obey the rules of RNA pairing and link only with a complementary molecule, or base pair, on the other strand. "We suspect we will find a whole family of stress-related proteins regulated this way," Kastan said.

Investigators showed that blocking the interaction at either end of the mRNA was enough to short-circuit RPL26 binding and lead to a dramatic fall in p53 protein levels in stressed or damaged cells.

Researchers used short pieces of DNA, so small they were absorbed by cells after simply being added to cell culture, to target the interactive bases and successfully disrupt formation of the double-stranded structure. Restoring the ability of the bases to bind the two ends of the mRNA restored RPL26 binding and stimulated p53 protein synthesis.

Work is underway to develop a mouse model to speed efforts to find or design small molecules that target this mechanism. "We have a long way to go in terms of drug development, but the better we can define the interaction between RPL26 and the double-stranded RNA structure the more likely we will be able to develop other small molecules to specifically block that interaction
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Contact: Summer Freeman
summer.freeman@stjude.org
901-595-3061
St. Jude Children's Research Hospital
Source:Eurekalert

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