The same sources thought to inflict oxidative stress on cells--pollution, diesel exhaust, smoking and obesity--also are associated with shorter telomeres, the protective tips on the ends of the chromosomal shoelace. A new study published today in Molecular Cell, provides the first smoking gun evidence that oxidative stress acts directly on telomeres to hasten cellular aging.
"Telomeres consist of hundreds of guanine bases, which are sinks for oxidation," said senior author. "Is it just a coincidence? Or could it be true that oxidizing those guanines in the telomeres is really contributing to shortening?"
Authors developed a method for zeroing in on the telomeres using a special light-activated molecule that latches onto the telomere and delivers localized free radicals--the molecular agent of oxidative stress--on command. They developed a chemoptogenetic tool that selectively produces 8-oxoG only at telomeres. Acute telomeric 8-oxoG formation increased telomere fragility in cells lacking OGG1, the enzyme that removes 8-oxoG, but did not compromise cell survival.
However, chronic telomeric 8-oxoG induction over time shortens telomeres and impairs cell growth. Accumulation of telomeric 8-oxoG in chronically exposed OGG1-deficient cells triggers replication stress, as evidenced by mitotic DNA synthesis at telomeres, and significantly increases telomere losses. These losses generate chromosome fusions, leading to chromatin bridges and micronucleus formation upon cell division. By confining base damage to the telomeres, authors show that telomeric 8-oxoG accumulation directly drives telomere crisis.
"One of the main challenges to targeting oxidative damage to specific loci in living cells has been achieving precise temporal and dose-control of this damage," the author said. "By combining telomere targeting with our optochemogenetic generation of singlet oxygen, we are able to selectively control when and how hard the oxidative stress is applied specifically at the telomere sites."
The researchers repeatedly exposed cultured cancer cells to this targeted oxidation procedure, mimicking conditions of environmental oxidative stress and inflammation, and, indeed, they saw the telomeres break and shorten with each cell division, despite repair efforts by the telomere lengthening enzyme telomerase.
As the DNA repair machinery tried to fix the broken telomeres, the ends of the chromosomes often fused together, destabilizing the genome and preventing cells from dividing properly.
Whereas telomere shortening spells bad news for healthy cells, the senior author said, the flipside is that targeting telomeres might offer a way to fight cancer. With short enough telomeres, cancer cells would stop dividing.
"If we can understand what causes telomere shortening and how cells compensate for that," the senior author said, "then we'll be in a better position to design intervention strategies that protect telomeres in healthy cells and target telomeres in cancer cells."
https://www.cell.com/molecular-cell/fulltext/S1097-2765(19)30316-8
Direct oxidative stress damage shortens telomeres
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