Telomeres glow at the end of chromosomes. Credit: Hesed Padilla-Nash and Thomas Ried of the NIH
New method may speed understanding of short telomere diseases and cancer and the new method they used to find it should speed discovery of other proteins and processes that determine telomere length. “We’ve known for a long time that telomerase doesn’t tell the whole story of why chromosomes’ telomeres are a given length, but with the tools we had, it was difficult to figure out which proteins were responsible for getting telomerase to do its work,” saysProf. Carol Greider, Ph.D (winner of the 2009 Nobel Prize in Physiology or Medicine for the discovery of telomerase.)
Figuring out exactly what’s needed to lengthen telomeres has broad health implications as shortened telomeres have been implicated in aging and in diseases eg lung and bone marrow disorders, while overly long telomeres are linked to cancer.
Until now researchers have used a time-consuming test for whether a given protein is involved in maintaining telomere length, a test that first requires blocking a suspected protein’s action in lab-grown cells, then getting the cells to grow and divide for ~3 months so that detectable differences in telomere length can emerge. In addition to being time consuming, the test could not be used at all for proteins whose loss would kill the cells before the 3-month mark.
•ADDIT assay measures telomerase-mediated addition at a single telomere •De novo telomere addition in mouse cells requires ATM kinase •ATM inhibition blocks bulk telomere elongation in both mouse and human cells •Excess activation of ATM by inhibition of PARP1 increases telomere addition
To find a better tool, grad student Stella Suyong Lee started with a concept used for measuring telomere length in yeast. The idea was to artificially cut mammalian cells’ telomeres, then detect elongation by telomerase – a test that would take less than a day, and could be performed even if the blocked proteins were needed for cells to divide. Transition from yeast to mammals involved a host of unforeseen technical difficulties, and the project took nearly 5yrs.
For their trial run of the new test, addition of de novo initiated telomeres (ADDIT), Greider’s group blocked enzyme ATM kinase, involved in DNA repair, in lab-grown mouse cells, and used ADDIT to find that it was needed to lengthen telomeres. They verified the result using the old, 3-month-long telomere test, and got the same result.
They also found that in normal mouse cells, a drug that blocks enzyme PARP1 would activate ATM kinase and spur telomere lengthening. This finding offers a proof of principle for drug-based telomere elongation to treat short-telomere diseases, such as bone marrow failure, Greider says – but she cautions that PARP1 inhibitor drug itself doesn’t have the same telomere-elongating effect in human cells as it does in mouse cells.
Greider’s group plans to use ADDIT to find out more about the telomere-lengthening biochemical pathway that ATM kinase is a part of, as well as other pathways that help determine telomere length. “The potential applications are very exciting,” Lee says. “Ultimately ADDIT can help us understand how cells strike a balance between aging and the uncontrolled cell growth of cancer, which is very intriguing.” http://www.eurekalert.org/pub_releases/2015-11/jhm-rdo111015.php
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