Beyond telomerase: another enzyme discovered critical to maintaining telomere length

New discovery expected to speed understanding of short-telomere-related diseases and cancer
November 13, 2015

ATM inhibition shortens telomeres and ATM activation elongates telomeres. (credit: Stella Suyong Lee et al./Cell Reports)

Johns Hopkins researchers report they have uncovered the role of an another enzyme crucial to telomere length in addition to the enzyme telomerase, discovered in 1984.

The researchers say the new test they used to find the enzyme should speed discovery of other proteins and processes that determine telomere length. Shortened telomeres have been implicated in aging and in diseases as diverse as lung and bone marrow disorders, while overly long telomeres are linked to cancer.

Their results appear in an open-access paper in the Nov. 24 issue of Cell Reports.

“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,” says Carol Greider, Ph.D., the Daniel Nathans Professor and Director of Molecular Biology and Genetics in the Johns Hopkins Institute for Basic Biomedical Sciences. Greider won 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, Greider notes. Telomeres naturally shorten each time DNA is copied in preparation for cell division, so cells need a well-tuned process to keep adding the right number of building blocks back onto telomeres over an organism’s lifetime.

But until now, researchers have been saddled with a limiting and 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 about three 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 three-month mark.

ATM kinase found needed to lengthen telomeres

Telomeres glow at the ends of chromosomes (credit: Hesed Padilla-Nash and Thomas Ried/NIH)

For their trial run of the new test, dubbed “addition of de novo initiated telomeres (ADDIT),” Greider’s group examined an enzyme called ATM kinase. “ATM kinase was known to be involved in DNA repair, but there were conflicting reports about whether it had a role in telomere lengthening,” says Greider.

Her team blocked the enzyme in lab-grown mouse cells, and used ADDIT to find that it was indeed needed to lengthen telomeres. They verified the result using the old, three-month-long telomere test, and got the same result.

The team also found that in normal mouse cells, a drug that blocks an enzyme called 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,” says graduate student Stella Suyong Lee, who conducted the research, which took nearly five years. “Ultimately ADDIT can help us understand how cells strike a balance between aging and the uncontrolled cell growth of cancer, which is very intriguing.”

Abstract of ATM Kinase Is Required for Telomere Elongation in Mouse and Human Cells

Short telomeres induce a DNA damage response, senescence, and apoptosis, thus maintaining telomere length equilibrium is essential for cell viability. Telomerase addition of telomere repeats is tightly regulated in cells. To probe pathways that regulate telomere addition, we developed the ADDIT assay to measure new telomere addition at a single telomere in vivo. Sequence analysis showed telomerase-specific addition of repeats onto a new telomere occurred in just 48 hr. Using the ADDIT assay, we found that ATM is required for addition of new repeats onto telomeres in mouse cells. Evaluation of bulk telomeres, in both human and mouse cells, showed that blocking ATM inhibited telomere elongation. Finally, the activation of ATM through the inhibition of PARP1 resulted in increased telomere elongation, supporting the central role of the ATM pathway in regulating telomere addition. Understanding this role of ATM may yield new areas for possible therapeutic intervention in telomere-mediated disease.