Academic journal article Environmental Health Perspectives

How Viruses Sabotage Silencing

Academic journal article Environmental Health Perspectives

How Viruses Sabotage Silencing

Article excerpt

The discovery and description of RNA silencing less than a decade ago has spawned a flood of research, revolutionizing the practice of functional genomics and leading to intensive exploration of its potential application to treat numerous diseases. RNA silencing was first noticed in plants when attempts to create transgenic plants that overexpressed a natural gene often had the opposite effect; later it was found to be an evolutionarily conserved defense mechanism against plant RNA viruses and other molecular parasites. Viruses, in turn, have evolved their own counterdefense mechanisms: proteins that suppress RNA silencing, allowing the virus to maintain its invasion of a plant. Until recently, the mechanism behind this suppression of silencing was a mystery, but researchers at the NIEHS and the Agricultural Biotechnology Center in Godollo, Hungary, have begun to unravel how some viruses neutralize silencing, shedding important new light on a complex molecular interaction.

In the 26 December 2003 issue of Cell, NIEHS investigator Tract M. Tanaka Hall, postdoctoral researcher Jeffrey Vargason, and Hungarian colleagues Jozsef Burgyan and Gyorgy Szittly elucidate the nature of viral counterdefense by solving the crystal structure of a known silencing suppressor, the tombusvirus Carnation Italian ringspot virus (CIRV) p19 protein, in complex with a 21-nucleotide small interfering RNA (siRNA), the workhorse bit of nucleic acid that drives the silencing process. The structure of a similar p19 protein found in another tombusvirus was published by Keqiong Ye, Lucy Malinina, and Dinshaw Patel, all of the Memorial Sloan-Kettering Cancer Center, in the 18/25 December 2003 issue of Nature. The slight differences in the structures have allowed researchers to draw further inferences about how a virus can interfere with RNA silencing.

There are two classes of plant siRNAs. The shorter ones, measuring 21-22 nucleotides, are responsible for detecting and destroying molecular invaders. The longer ones, measuring 24-26 nucleotides, are suspected to be more involved with regulating retrotransposons and DNA methylation. The structure of p19 reveals that the protein selectively recognizes silencing siRNAs by measuring their length. Tryptophan residues (Trp39 and Trp42) on the protein act like molecular calipers, forming a so-called stacking interaction with the ends of the end base pairs of the shorter siRNAs. By binding to the silencing siRNAs, the protein in effect sequesters them, rendering them incapable of carrying out their silencing mission and allowing the virus to run rampant within the plant.

The protein can also bind to the longer siRNAs, but much more weakly. …

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