World News – AU – Embryonic stem cells have their own strategy for protecting the chromosome ends

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26th. November 2020

from the National Cancer Institute

According to new research by CCR scientists, embryonic stem cells have a unique way of protecting their telomeres, the structures at the ends of chromosomes that shorten with each cell division. A research team led by Eros Lazzerini Denchi, Ph. D.. . , an NIH Stadtman researcher at the CCR Laboratory of Genomic Integrity, found that embryonic stem cells, not like most cells, treat exposed telomeres as damaged DNA, but instead use genes that are normally only used at the earliest stages of development to fight off unwanted DNA repairs. The team’s results, derived from studies on mouse embryonic stem cells, will be announced on Jan.. November 2020 published in Nature.

By uncovering an unexpected way in which cells can protect their telomeres, the new findings can help explain a survival strategy for some cancer cells that needs to find a way to bypass the limits of growth caused by the natural shortening of the Telomeres arise in old age.

Embryonic stem cells, which arise early in the development of an embryo, have the unique ability to become virtually any of the body’s specialized cell types. Lazzerini Denchi and colleagues first discovered their unusual approach to protecting telomeres when they found that cells can survive without a protein called TRF2, which attaches to and protects chromosome tips. The protein is essential for hundreds of different cell types. Without them, exposed chromosome tips trigger faulty activation of the repair pathways for DNA damage, which sew the unprotected ends together. Chromosomes fuse and cells lose the ability to divide. When Lazzerini Denchi’s team removed TRF2 from embryonic stem cells, the chromosomes retained their integrity and the cells continued to multiply.

« We expected the cells to be really sick, but instead they were perfectly fine, » he says. However, once the researchers induced the TRF2-missing stem cells to differentiate into a more advanced stage of development, they behaved like any other cells without TRF2: chromosomes fused and the cells quickly died.

In subsequent experiments led by postdoctoral fellow Marta Markiewicz-Potoczny, the researchers found that embryonic stem cells responded in eliminating TRF2 by activating unprotected telomeres by activating a number of genes that are normally not activated until shortly after fertilization The embryo consists of only two cells. « The moment we mess with telomeres, embryonic stem cells begin to express some genes that are normally expressed very early in embryogenesis, » says Lazzerini Denchi. « These are genes that are normally turned off in embryonic stem cells and in every other state of differentiation, but in this case they have been used widely. « 

This response appeared to be key to the cells’ ability to thrive without TRF2. While cell division gradually shortens the telomeres in adult cells, their sequences are continuously lengthened in the early stages of development. By reactivating genes that were used early in development, embryonic stem cells may be able to lengthen exposed telomeres instead of triggering a DNA damage response, the researchers say.

The team’s experiments showed that one of these developmental genes, ZSCAN4, appears to be an integral part of embryonic stem cells’ strategy to protect their chromosome ends. This gene is sometimes active in cancer cells, which could help them evade normal growth restrictions imposed by the shortening of the telomeres.

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Stem cells, telomeres, chromosomes, research, embryonic stem cells