Resetting The Clock: New Enzyme Found To Repair Telomeres

A HeLa Immortal cell line used in laboratory settings. Immortal cell lines need to lengthen their telomeres to divide indefinitely

The telomere caps on the end of your chromosomes unravel bit by bit with every cell division, and if they’re not repaired division eventually stops altogether. Cells like stem cells express special enzymes to lengthen these caps, and we’ve now found another one that does the job. 

A key player in aging?

Many factors drive aging, but telomeres play a key role in allowing cells to divide at all and are therefore a major potential anti-aging target. Aging is a murder mystery case involving a range of perpetrators, but telomere shortening has been connected to multiple age-related diseases and many scientists believe we’ll have to find ways to repair telomeres if we want to live longer.

Shortened telomeres can cripple your ability to regenerate tissue

Telomerase isn’t the only player in town

We already know one enzyme that repairs telomeres, and it’s fittingly called ‘telomerase’. This enzymes works hard in cells that need to divide frequently. The problem with telomerase is we know cancer cells have to find ways to repair their telomeres to survive, and research has shown some cancer cells don’t need telomerase to do so. So what are they using instead? 

Cancer can use a different mechanism altogether

Cancer can use a different mechanism we’re still studying today called ALT – Alternative Lengthening of Telomeres. There is hope that by understanding this mechanism more, we’ll be able to specifically target cancerous populations and halt them in their tracks. About 10% of cancers appear to deploy ALT to survive, which means any drugs targeted against telomerase simply don’t work. Considering currently about 820,000 deaths happen every year due to ALT cancers, it’s a problem we need to work on. Uncovering how they do it might also help us learn new ways of tackling shortening telomeres. 

“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” 

Now we know a 2nd enzyme can repair telomeres too

Telomerase was discovered in 1984 and the groundbreaking work even won a Nobel Prize. Researchers soon noted that telomerase wasn’t the only mechanism responsible for telomere lengthening, but laborious testing methods made the problem time consuming to study; it could take up to 3 months to observe lengthening in the lab. 

A new method to study telomere lengthening in a day was therefore developed at the John Hopkins Institute, called addition of de novo initiated telomeres (ADDIT). The test involves cutting yeast telomeres and then observing them to catch any repair mechanisms going on. An enzyme called ATM Kinase normally involved with DNA repair has been suspected for some time to help lengthen telomeres as well, and after the new test was perfected they tested this new enzyme for activity. It was indeed lengthening the telomeres. 

A new mechanism to act on

When the team tested a drug that inhibits an enzyme called PARP1 , in mice cells it appeared to boost ATM Kinase repair activity and surprisingly helped lengthen the telomeres. The drug didn’t have the same effect in humans cells, but more research could uncover alternatives that do. Mice have longer telomeres than humans despite living extremely short lives, which shows us there’s more involved with aging. 

“The potential applications are very exciting. Ultimately ADDIT can help us understand how cells strike a balance between aging and the uncontrolled cell growth of cancer, which is very intriguing.”

We’ve found some correlation between telomere length and age, but it’s extremely variable

Hope and caution ahead

Short telomeres are linked to generalised aging and other conditions involving the bone marrow and even lung disease. While long telomeres are also linked to cancer, there is still debate over whether they increase cancer risk. Some now believe that longer telomeres are good if a cell is healthy and mostly damage free, but that giving a damaged cell longer telomeres is a recipe for cancer – because you’re essentially giving them a ‘get out of jail free card’.  While telomere lengthening has shown promise in mice, until we’ve worked out exactly how much they contribute in humans, many scientists are urging caution. 

Read more at MedicalXpress