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Scientists discover new, noncommittal mechanism of drug resistance
Date:7/27/2014

nced the gene FKBP12 -- the target of FK506 -- to look for mutations that would confer drug resistance.

However, she couldn't detect any mutations in about a third of the isolates. What's more, Wall found that many of the mutants kept "disappearing," looking less like mutants and more like their parents after she took the drug away.

"This is an example of something you might find in the laboratory and just throw away," said Silvia Calo, Ph.D., lead study author and postdoctoral fellow in the Heitman and Cardenas labs. "You look for mutants in one gene and when you don't find a mutation in some of the isolates, you decide not to work on those anymore and instead focus on others. But we wanted to know what was going on."

The researchers began to wonder whether a phenomenon known as RNA interference or RNAi could be the cause of this unstable drug resistance. RNAi uses bits of RNA -- the chemical cousin of DNA -- to silence specific genes. Though RNAi doesn't exist in every organism, the researchers knew it was active in M. circinelloides because of the pioneering work of their collaborators Rosa Ruiz-Vazquez and Santiago Torres-Martinez, with whom Calo trained at the University of Murcia, Spain.

So Calo looked for the presence of small RNAs -- a signature of RNAi -- in the drug resistant isolates. She didn't find small RNAs in the isolates that contained mutations in FKBP12, but she did find them in those lacking mutations. Importantly, Calo found that these small RNAs only silenced the FKBP12 gene and not any other loci in the genome. The results demonstrate that M. circinelloides can develop drug resistance two different ways, either stably through permanent mutations or transiently through reversible epimutations.

"This plasticity enables an organism to reverse epigenetic mutations when selective pressures are relaxed," said Calo. "Otherwise, silencing a gene when it doesn't need to be silenced would be a waste of ene
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Contact: David Jarmul
david.jarmul@duke.edu
919-684-6815
Duke University
Source:Eurekalert  

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