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Enzyme increase prolongs life span of fruit flies

ADAR promotes the de-silencing of transposons, yielding a 20 percent increase in flies’ life spans

Extending an organism’s life simply by increasing the concentration of an enzyme may be possible, thanks to groundbreaking results from a study on gene expression led by Robert Reenan, professor of biology, in collaboration with several graduate students and field experts.

The idea for the research was conceived seven years ago when Yiannis Savva GS discovered ADAR, a specific enzyme on a site of chromosome four. This observation puzzled both him and Reenan.

Each time RNA was exposed to ADAR, the enzyme would target double-stranded sections of RNA exclusively. This peculiarity would become the centerpiece of Savva’s thesis paper.

In the present study, the researchers found that when ADAR was added to a specific transposon — a piece of genetic material — there was a 20 percent increase in median life span and a change in eye color pigmentation in both male and female flies.

A significant number of genes have transposable elements within them, and even more have transposons around them. Hundreds of genes in flies and thousands of genes in humans have transposons.

Transposons are typically surrounded by chromatin, tight bundles of DNA, that serve to mute the transposon’s code. The enzyme ADAR acts to loosen the bonds of these chromatin bundles. By increasing these levels of ADAR, more “undesirable” transposons were free to jump from gene to gene.

When multiple transposons became mobile, they tended to end up next to each other, creating double-stranded RNA sequences. So when ADAR was introduced to the genes of a fruit fly, it was observed to bind to the double-stranded sections of RNA.

Typically when RNA is being edited, an organism’s genome has a mechanism for pinpointing the double-stranded RNA sequence and chopping up the RNA into snippets that can wrap around the transposon. A mechanism within the organism then takes these bits of RNA and searches for similar RNA pieces to eliminate. Not all transposons in an organism’s genome are silenced simultaneously, leading to variation from individual to individual.

“This technique effectively stifles the transposable elements and prevents them from filling up the entire genome with junk DNA, like a ‘genomic immune system,’” Savva said.

ADAR loosens the tightly regulated system, inducing a chemical change that alters the identity of  a component of DNA, so that it is viewed as a different component by the rest of the cell and is no longer identified as a target by the RNA silencer.

“The small RNAs are like police artist sketches, and the dicers are like the sketch artists, and they hand the sketch off ,” Reenan said. “We have shown that ADAR interferes with that process.”

One obstacle that the group encountered was trying to capture a certain image of the fruit fly’s genome from a microscope. Part of the genome was removed by genetic engineering so that ADAR could not bind to the RNA anymore. Half of the chromosome that ADAR could still bind to would appear green, and the removed half would appear red. But when the researchers ran their test, the red and green portions were scattered and speckled in a random fashion. Searching numerous chromosomes and taking many snapshots, they eventually obtained a snapshot of the clearly defined separation.

“It took probably 100 slides of DNA to see the desired arrangement,” Savva said.

It may take several years to apply the results of the study to the human genome, given the complexity of gene expression, Reenan said.


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