Telomeres protect the ends of our chromosomes, much like the plastic cap at the end of a shoelace that prevents the lace from unravelling. Over a cell's lifetime, telomeres get gradually shorter with each cell division and therefore the protective cap becomes less and less effective. If they get too short, it is a signal for the cell that its genetic material is compromised and the cell stops dividing.
Telomere shortening and reduced cell division are considered a hallmark of ageing and likely contribute to the ageing process. However, telomere shortening is also a defense mechanism against cancer because highly proliferative cells can only divide when their telomeres do not shorten. Therefore, telomere shortening is a double-edged sword and has to be carefully regulated to strike a balance between ageing and cancer prevention. When a telomere accidentally gets cut short early in a cell's lifetime, it needs to be fixed so that the cell doesn't become senescent too early. When critically short telomeres arise in the absence of telomerase, they can be repaired by homology-directed repair (HDR) to prevent premature senescence onset. It is unclear why specifically the shortest telomeres are targeted for HDR.
Researchers have further uncovered the secrets of telomeres, the caps that protect the ends of our chromosomes. They discovered that an RNA molecule called TERRA (telomeric repeat-containing RNA) helps to ensure that very short (or broken) telomeres get fixed again. The work, which was recently published in the journal Cell, provides new insights into cellular processes that regulate cell senescence and survival in ageing and cancer.
TERRA accumulates as HDR-promoting RNA-DNA hybrids (R-loops) specifically at the ends of critically short telomeres by binding directly to the DNA and signals to the cell that these telomeres should be repaired, allowing the cell to carry on dividing.
At long telomeres TERRA is rapidly removed with the help of proteins Rat1 and RNase H2. These proteins bind preferentially to the long telomeres and ensure that TERRA is removed, but they are not present at the critically short telomeres, which means that TERRA remains for a longer time. This mechanism ensures the subsequent repair of the short telomere, which is crucial for the cell to survive and keep dividing.
The work was carried out in yeast; however, telomeres and TERRA are found across all organisms with linear chromosomes. The researchers expect their work to be applicable to humans as well. Their next step will be to look into these processes in human cells and interrogate their implications for ageing and cancer.
Mechanism of shorter telomere repair and cellular senescence prevention
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