Volume 23 | Issue 12 | Page 51
By Jef Akst
Translation Revelation
More findings confirm that small RNAs work in mysterious ways.
Nearly 20 years after its discovery, RNA interference (RNAi) is part of biology’s orthodoxy. Small RNA molecules can disrupt gene expression by degrading messenger RNAs (mRNAs) on their way to becoming proteins, or otherwise interfering with translation. But the discovery that these same small RNA molecules might be able to do just the opposite—enhance gene expression—was somewhat heretical.
In 2007, molecular biologist Shobha Vasudevan of Yale University and her colleagues produced the unanticipated findings: Small RNA molecules known to be involved in RNAi, known as microRNAs (miRNAs), can activate translation, promoting the conversion of mRNAs to proteins. It was a “surprise finding,” Vasudevan recalls.
Fluorescent FT protein in the phloem of an Arabidopsis plant.
© Jean-Francois Podevin / Photo Researchers, Inc.
Further investigation revealed that activation occurred only during cell-cycle arrest, induced by serum starvation. In actively growing cells, on the other hand, miRNAs suppressed translation. The exact mechanism of activation is unclear, Vasudevan says, but it appears to involve the recruitment of Argonaute (AGO) proteins—known participants in the RNAi pathway—and fragile X mental retardation–related protein 1 (FXR1). These proteins combine with the miRNA to form complexes that bind to the 3' untranslated region (3'-UTR) of the mRNA of tumor necrosis factor-α (TNFα) to initiate translation.
This discovery was hot on the heels of another unexpected finding—that of RNA activation (RNAa) at the level of gene transcription. Just one year earlier, molecular biologists Long-Cheng Li and Robert Place and their colleagues at the University of California, San Francisco, found that small RNAs could switch on gene transcription1—a finding that was corroborated just a few months later by a group of researchers working independently at the University of Texas Southwestern Medical Center at Dallas.2 (See the May 2009 issue of The Scientist.) And last year, additional research revealed more of the mysterious qualities behind translation activation by miRNA.
“These papers are making us look at miRNAs as a far more versatile system of regulating gene expression,” says Vasudevan, now at Massachusetts General Hospital and Harvard Medical School.
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