Studies find new details about telomeres
They’re the barometers of cellular aging.
When you smoke, are exposed to pollution, are stressed, obese, fail to exercise or follow an unhealthy diet, research shows that telomeres — the end caps to our chromosomes — can shorten more quickly, accelerating the age-related breakdown of your cells. Reducing stress, exercising and eating healthfully can slow that breakdown, even adding years to your life.
Now two University of Pittsburgh researchers — biochemist Patricia Opresko and cell biologist Roderick O’Sullivan — have published studies that explain more about how damage and disease interfere with the normal shortening of telomeres each time a cell divides as a person gets older.
Ms. Opresko said her team investigated the mechanism of oxidative stress on the shortening of telomeres. Oxidative stress is an excess of free radicals (molecules with an odd number of electrons that can can be formed when oxygen interacts with certain molecules) and they can react with the segments of DNA that make up telomeres and their DNA building blocks, causing cell damage.
The oxidative stress was artificially induced in the study by growing cells in a high-oxygen environment, she said, which increased the number of free radicals. In the body, antioxidants protect cells by safely interacting with free radicals. Cell damage from a buildup of free radicals is associated with inflammation and raises the risk of cancer and other diseases.
In the study, when the damage was applied to the telomeres, more of the enzyme telomerase was produced and a repair process lengthened the telomeres. However, Ms. Opresko explained, the research found that when oxidative stress was applied to the DNA building blocks — whose job is to restore and repair DNA — repair was blocked.
“It gets stuck in its tracks,” said Ms. Opresko, whose study in the journal Nature Structural and Molecular Biology was funded by the National Institutes of Health and other sources. “It can’t extend any further.” The result was
telomere shortening.
Further investigation may point to targeting DNA building blocks in cancer cell telomeres instead of depleting telomerase, the enzyme related to tumor growth in 85 percent of all cancers, the researcher said. She speculated there may a way to prevent the cleaning out of damaged building blocks in cancer cells so that telomerase cannot restore the shortened telomeres and the cancer cells die.
“Telomeres are really at the axis of aging and cancer. … We want our healthy cells to divide and our cancer cells to stop. Telomeres are really the key here.”
Another way that telomeres in cancer cells sidestep the normal shortening process was discovered by Roderick O’Sullivan’s team at Pitt, whose findings were published in the journal Cell Reports. Grants from NIH, Pitt and French nonprofits supported the study. Ms. Opresko was a co-author.
Mr. O’Sullivan explained that cancer cells must do two things: 1) acquire mutations that allow them to circumvent the body’s disease protection system and 2) maintain length in their telomeres.
He said his team found out more about the alternate way that cancer cells keep telomeres long, without using telomerase.
“They’re pulling resources from within the cell to get the job done. They’re hijacking DNA repair pathways … to be sure they are replicated and maintained.”
“Patty is talking about the enzyme essential for 85 percent of cancer,” Mr. O’Sullivan said, referring to his Pitt colleague. “What we’re working on is the mechanism for the remaining 15 percent.” It’s called alternative lengthening of telomeres, or ALT.
The researchers used a new technique to identify proteins that were found close to and possibly related to the telomere lengthening in cancer cells. They found 139 proteins unique to ALT-activated cells. One enzyme was identified, but unexpected — it’s usually active only in cells damaged by ultraviolet light.
“We found this protein seems to be co-opted to maintain this alternative. We found a pathway, a network of proteins that focus on this core, from UV damage,” Mr. O’Sullivan said.
“We hypothesized [that this pathway] was essential for survival of these 15 percent of cancers. … We weren’t treating them with damaging agents. They coopted these mechanisms.”
Cancer biologist Rachel Flynn at the Boston University School of Medicine has also published work on proteins involved in ALT pathways, and she said the O’Sullivan lab’s work sheds new light on the complex ALT mechanism.
“I think this is a really great contribution to understanding ALT the way we haven’t before,” she said. One protein in the list was previously characterized by Ms. Flynn’s group.
“The ALT pathway is active in some of the more aggressive cancers,” she said, such as the brain cancer glioblastoma. “These cancers have a poor prognosis.”
Mr. O’Sullivan said these ALT pathways come with late mutations in a cancer. Telomerase is completely shut down, he said. “The cancer cell is desperate to survive; trying every trick in its book. … There’s some evidence to suggest this ALT mechanism results in chemo resistance or latestage tumors. It’s still a huge question.”
In the future, Ms. Opresko said, “with personalized medicine, and next-generation sequencing, we will be able to [determine the] genome of these cancers and find their Achilles’ heel. …
“If you can characterize the cancer cells you could predict what therapy they’d be sensitive to. We’re hoping that telomeres’ length might be a biomarker.”