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Telomere protection in stem cells

In a new study published in Nature, researchers at the Francis Crick Institute have uncovered the unique way stem cells protect their telomeres.

Telomeres

Mammalian telomeres are specialised structures at the ends of chromosomes that protect chromosome ends from aberrant DNA repair and ensure healthy division of cells. Researchers have long assumed that mechanisms of telomere protection are conserved in somatic and stem cells. However, the evidence to support this is lacking. For the last 20 years, scientists have been working on understanding how telomeres protect chromosome ends from being incorrectly repaired and joined together. This mechanism has important implications for our understanding of cancer and ageing. In healthy cells, this protection is very efficient. Nonetheless, as we age our telomeres get progressively shorter, eventually losing some of these protective functions. This contributes to the progressive decline in our health and fitness as we age. Conversely, telomere shortening poses a protective barrier to tumour development. Cancer cells must bypass this in order to divide indefinitely.

In somatic cells, researchers know that the protein TRF2 helps protect telomeres by binding to and stabilising a loop structure (T-loop), which masks the end of the chromosome. When the protein is removed, these loops do not form and the chromosome ends fuse together, ultimately killing the cell.

Stem cell telomere protection

In this recent study, Crick researchers found that when the TRF2 protein is removed from mouse embryonic stem cells, T-loops continued to form, chromosome ends remained protected and the cells were largely unaffected. In other words, TRF2 protein is largely dispensable for telomere protection. These cells instead activated an attenuated telomeric DNA damage response that lacks accompanying telomere fusions, and propagates for multiple generations

Philips Ruis, first author and PhD student at the Crick, stated:

“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.”

The team also found that telomeres in stem cells with T-loops but without TRF2 were still protected. They showed that embryonic stem cells form T-loops independently of TRF2. This revealed why TRF2 was dispensable for end protection during pluripotency. It also suggests that the T-loop structure itself has a protective role.

This data establishes that telomere protection is solved by distinct mechanisms in pluripotent and somatic tissues. The researchers will continue this work to understand the precise mechanisms of telomere protection in both somatic and embryonic cells. A better understanding of how telomeres work will offer crucial insight into the underlying processes that lead to premature ageing and cancer.

Image credit: By Image Team – canva.com


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