Telomere T-loops Prevent Chromosome Damage

T-loops at the ends of telomeres play a vital protective role preventing irretrievable damage to chromosomes, according to researchers from The Francis Crick Institute. Their paper, published today in Nature, showed how the winding and unwinding of t-loops prevents chromosomes from being recognized as DNA damage.

A significant challenge for maintaining linear chromosomes is that the DNA end must be prevented from being detected as DNA damage. This problem is solved by telomeres. One way that telomeres are thought to protect the end of the chromosome is by adopting a lasso-like t-loop structure, which acts to bury the DNA end within the telomere and mask it from being detected as DNA damage. These loops are formed by the telomeres folding back on themselves at the end of the chromosome and can be wound or unwound.

"While telomeres are known to play a vital role in protecting DNA and allowing cells to divide, there has been a cloud of uncertainty surrounding t-loops, their function and importance. This is a question we wanted to resolve with this study," says Panagiotis Kotsantis, one of the authors of the paper.

The study discovered how important it is for these t-loops to be wound or unwound at the correct stage of the cell cycle. If DNA replication occurs while the t-loop remains wound up, this creates a problem as the advancing replication fork collides with the t-loop, triggering catastrophic loss of the telomere and damage to the chromosome end.

On the other hand, by manipulating the telomere so that the t-loop is inappropriately unwound throughout all stages of the cell cycle, the researchers discovered that the chromosome ends are now unmasked and are detected as DNA damage. This showed that t-loops are important for protecting the ends of chromosomes.

"Ensuring that these loops are unwound during DNA replication and then re-wound for all other stages in the cell cycle, is essential to stop chromosomes being damaged. It's a really intricate process, and the consequences if it goes wrong can be disastrous for the cell," explains Simon Boulton, senior author.