Study shows how telomeres protect chromosome ends

Telomeres are essentially specialized structures that are located at the end of chromosomes. These structures not only protect human DNA but also ensure a healthy cell division.

Chromosome fusions in TRF2-knockout MEFs. The Francis Crick Institute.

Now, according to a new research work performed by scientists from The Francis Crick Institute, the mechanisms of telomere protection are unexpectedly special in stem cells.

For the past two decades, investigators have been actively working to figure out how telomeres guard the ends of the chromosomes against being wrongly repaired and linked together, as this holds significant implications for interpreting aging and cancer.

This protection with regard to healthy cells is extremely efficient, but as humans age, their telomeres become increasingly shorter, and they ultimately become so short that they end up losing a few of these protective functions. In the case of healthy cells, this plays a crucial role in the continuous decline of people’s health and fitness as they age.

On the other hand, telomere shortening offers a protective barrier to the development of tumors, which must be solved by cancer cells to divide infinitely. In the case of somatic cells, which refer to all the cells found in the adult body excluding the gametes and stem cells, it is already known that the telomere is protected by a protein known as TRF2.

The protein performs this activity by attaching to and stabilizing a loop structure, known as a t-loop, which conceals the chromosome ends. Upon removing the TRF2 protein, these loops are no longer formed and the ends of the chromosomes combine together, resulting in “spaghetti chromosomes” and destroying the cell.

But in the new study, the researchers from The Francis Crick Institute have discovered that when this TRF2 protein is eliminated from mouse embryonic stem cells, the ends of the chromosomes remain protected, the t-loops continue to develop, and the cells remain largely unaffected.

When embryonic stem cells distinguish into somatic cells, this exclusive mechanism of end protection is lost and t-loops, as well as chromosome end protection, become dependent on the TRF2 protein. This indicates that stem cells and somatic cells protect their ends of the chromosomes in basically different manners.

Now we know that TRF2 isn’t needed for t-loop formation in stem cells, we infer there must be some other factor that does the same job or a different mechanism to stabilise t-loops in these cells, and we want to know what it is.”

Philip Ruis, Study First Author and PhD Student, DNA Double Strand Breaks Repair Metabolism Laboratory, The Francis Crick Institute

Ruis continued, “For some reason, stem cells have evolved this distinct mechanism of protecting their chromosomes ends, that differs from somatic cells. Why they have, we have no idea, but it's intriguing. It opens up many questions that will keep us busy for many years to come.”

Unraveling the protective properties of t-loops

Moreover, the researchers have helped to explain years of uncertainty about whether these t-loops themselves play a significant role in guarding the ends of the chromosomes. They observed that telomeres found in stem cells with t-loops but without the TRF2 protein are still protected; this indicates that the t-loop structure itself plays a protective role.

Rather than totally contradicting years of telomere research, our study refines it in a very unique way. Basically, we’ve shown that stem cells protect their chromosome ends differently to what we previously thought, but this still requires a t-loop.”

Simon Boulton, Study Author and Group Leader, DNA Double Strand Breaks Repair Metabolism Laboratory, The Francis Crick Institute

Boulton continued, “A better understanding of how telomeres work, and how they protect the ends of chromosomes could offer crucial insights into the underlying processes that lead to premature aging and cancer.”

The researchers worked in association with Tony Cesare based in Sydney and other scientists across The Francis Crick Institute, including Kathy Niakan from the Human Embryo and Stem Cell Laboratory, and James Briscoe from the Developmental Dynamics Laboratory at The Francis Crick Institute.

This is a prime example of what the Crick was set up to promote. We've been able to really benefit from our collaborator’s expertise and the access that was made possible by the Crick’s unique facilities.”

Simon Boulton, Study Author and Group Leader, DNA Double Strand Breaks Repair Metabolism Laboratory, The Francis Crick Institute

The team will continue the study in an effort to comprehensively understand the mechanisms of telomere protection in both embryonic and somatic cells.