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Telomeres are specialized structures at the ends of chromosomes that protect our DNA and ensure healthy cell division. According to a new study by Francis Crick Institute researchers published in Nature, telomere protection mechanisms are surprisingly unique in stem cells.
For the past 20 years, researchers have worked to understand how telomeres protect the ends of chromosomes from being incorrectly fixed and joined together because this has important implications for our understanding of cancer and aging.
In healthy cells, this protection is very efficient, but as we age our telomeres progressively shorten, until they become so short that they lose some of these protective functions. In healthy cells, this contributes to the progressive decline in our health and fitness as we age. Conversely, telomere shortening represents a protective barrier to tumor development, which cancer cells must resolve in order to divide indefinitely.
In somatic cells, which are all cells in the adult body except stem cells and gametes, we know that a protein called TRF2 helps protect telomeres. It does this by binding and stabilizing a ring structure, called a t-loop, which masks the end of the chromosome. When the TRF2 protein is removed, these rings do not form and the ends of the chromosome fuse together, leading to “spaghetti chromosomes” and killing the cell.
However, in this latest study, Crick’s researchers found that when the TRF2 protein is removed from mouse embryonic stem cells, T-loops continue to form, the ends of the chromosomes remain protected, and the cells are largely unaffected.
When embryonic stem cells differentiate into somatic cells, this unique end protection mechanism is lost and both T-loops and chromosomal end protection become TRF2 dependent. This suggests that somatic and stem cells protect their chromosomal ends in fundamentally different ways.
“We now know that TRF2 is not needed for t-loop formation in stem cells, we infer that there must be some other factor doing the same job or a different mechanism to stabilize the t-loops in these cells, and we want to know what. it’s about, ”says Philip Ruis, first author of the article and a doctoral student at the DNA Double Strand Breaks Repair Metabolism Laboratory at Crick.
“For some reason, stem cells have developed this distinct protective mechanism of chromosomal ends, which differs from somatic cells. Because they have it, we have no idea, but it is intriguing. It opens up many questions that will keep us busy for many years to come. . “
The team also helped clear up years of uncertainty whether the T-rings themselves play a role in protecting chromosomal ends. They found that telomeres in stem cells with t-loop but without TRF2 are still protected, suggesting that the t-loop structure itself plays a protective role.
“Rather than totally contradict years of telomere research, our study refines it in a very unique way. Basically, we have shown that stem cells protect their chromosomal ends differently than we previously thought, but this still requires a t-loop, ”says Simon Boulton, author of papers and group leader in the DNA double-strand break repair metabolism laboratory at Crick.
“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 team worked in collaboration with Tony Cesare in Sydney and other Crick researchers, including Kathy Niakan, of the Human Embryo and Stem Cell Laboratory, and James Briscoe, of Crick’s Developmental Dynamics Laboratory. “This is a great example of what Crick was set up to promote. We were able to take advantage of the experience of our collaborators and the access made possible by Crick’s unique facilities,” says Simon.
Researchers will continue this work, with the aim of understanding in detail the protective mechanisms of telomeres in somatic and embryonic cells.
Reference: Ruis P, Van Ly D, Borel V, et al. Protection of the chromosomal end independent of TRF2 during pluripotency. Nature. 2020. doi: 10.1038 / s41586-020-2960-y
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