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Salk scientists open new window into how cancers override cellular growth controls
Date:3/21/2012

percent of cancers that use the ALT pathway. In fact, some evidence suggests that drugs targeting telomerase might actually increase ALT, making the need for ALT inhibitors more pressing."

The new study stems from a 2008 study from the Karlseder lab that was published in Cell. In that paper, they mutated a gene encoding a telomere-binding protein in roundworms. The resulting mutants displayed functional, but slightly scruffier-looking telomeres than those built by telomerase. That was a strong hint that when forced, worm cells, like human cells, can turn on the ALT pathway.

For the new study, the team pushed the mutant worms' survival capacity to the limit. This time they knocked out a second gene, telomerase itself, and found that these double mutants could reproduce continuously without undergoing senescence. Over the past 3 years a strain of double mutant worms has propagated for over 180 generations.

The group then used biochemistry to confirm that the worms depend totally on ALT for telomere maintenance. The telomeres of double mutants were more sloppily constructed than superior, telomerase-made caps and were similar in length and overall structure to chromosome caps displayed by human cancer cells that employ ALT.

The double mutant worms also contained wisps of telomeric DNA, called c-circles, that are unique by-products of ALT, further evidence that they were persisting via ALT.

Intriguingly, other investigators have reported that c-circles are present in the blood of human bone cancer patients and could potentially serve as a diagnostic for cancers that depend on the ALT rather than the telomerase pathway.

Although the worms are living long, species-wise, they are not quite prospering---- which is exactly what one would expect. The study reports that the double mutants have fewer offspring than normal worms, which is how roundworms exhibit "stress." And many have fused chromosomes, a likely outco
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Contact: Andy Hoang
ahoang@salk.edu
619-861-5811
Salk Institute
Source:Eurekalert  

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