Oxidative stress appears to damage the DNA 'building blocks' used to repair telomeres - preventing additional blocks being added
Previous research has indicated that telomere loss appears to accelerate under conditions of high oxidative stress, but exactly how wasn't clear. Researchers initially believed that this was due to interactions between these reactive molecules and the enzyme telomerase, which is responsible for lengthening telomeres. A new study has revealed that it's in fact due to DNA damage, rather than the enzyme itself.
Corrupting the building blocks
When the effect of increased oxidative stress (a larger presence of free radical molecules) were examined in the laboratory, it was found that telomerase activity itself actually increased under these conditions. This was the opposite of the initial theory. Damage to the enzyme itself actually spurred the enzyme to work harder.
A breakthrough came when the team analysed the effect of oxidation on the DNA bases, or nucleotides, that telomerase recruits to add on to telomeres. One specific base in particular, Guanine, appeared to inhibit the telomere lengthening process when it had been oxidised. Telomerase is able to utilise these oxidised Guanine blocks to form a new stretch of DNA, but once this is added it prevents any additional blocks from being added afterwards - inhibiting healthy telomere replenishment.
"The new information will be useful in designing new therapies to preserve telomeres in healthy cells and ultimately help combat the effects of inflammation and aging. On the flip side, we hope to develop mechanisms to selectively deplete telomeres in cancer cells to stop them from dividing. We found that oxidation of the DNA building blocks is a new way to inhibit telomerase activity, which is important because it could potentially be used to treat cancer"
What does this mean?
Oxidative stress is very complicated, and some experiments have suggested that a slight rise in stress actually lengthens lifespan by increased cellular hardiness. However, it may be that too much, or too much in a specific region of the cell, actively inhibits telomerase activity and contributes to telomere attrition. Telomeres are absolutely essential for normal cellular division, and short telomeres drive inflammation, senescence and tissue loss as we get older. Conversely, increased telomerase activity is a common feature of cancer cells, which means this research has implications for both cancer drug development and telomere protecting therapies. If we can work out a way of protecting these Guanine blocks from damage then we may actively boost telomerase function, which speeding up their oxidation could inhibit cancer growth.
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