Telomerase Controller
Another step towards solving the mystery of aging and cancer
Maria Tolmacheva, XX2 century
The human body consists of trillions of living cells. It ages as these cells stop reproducing and dividing. Scientists have long known that genes affect cell aging and human lifespan, but exactly how this happens remains unclear. The results of the new study allowed us to solve a small piece of this puzzle, which brought scientists one step closer to understanding the mechanism of aging.
A research team led by Jiyue Zhu, a professor at the College of Pharmacy and Pharmaceutical Sciences, recently identified a DNA region known as VNTR2-1, which appears to control the activity of the telomerase gene. This gene, as shown in the work, prevents the aging of certain types of cells. The study is published in the journal Proceedings of the National Academy of Sciences (Xu et al., Polymorphic tandem DNA repeats activate the human telomerase reverse transcriptase gene).
The telomerase gene controls the activity of the telomerase enzyme, which helps to build telomeres – caps at the end of each DNA strand that protect chromosomes inside our cells. In normal cells, the telomere length becomes slightly shorter each time the cells duplicate their DNA before dividing. When telomeres become too short, cells can no longer divide, which leads to their aging and death. However, in some types of cells – including reproductive and cancer cells – the activity of the telomerase gene ensures the restoration of telomere length when copying DNA. In fact, this is what triggers the aging clock in the offspring, but it is also the reason that cancer cells can continue to multiply and form tumors.
Knowing how the telomerase gene is regulated and activated and why it is active only in certain types of cells may in the future be the key to understanding how people age, as well as how to stop the spread of cancer. That is why Zhu has been exclusively studying this gene for the last 20 years of his scientific career.
According to Zhu, his team's latest discovery that VNTR2-1 helps control the activity of the telomerase gene is particularly noteworthy because of what part of the DNA this gene represents.
"Almost 50% of our genome consists of repeating DNA that does not encode a protein. These DNA sequences are usually regarded as the "junk DNA" or "dark matter" of our genome, and they are difficult to study. Our study shows that one of these units actually has a specific function – it enhances the activity of the telomerase gene",
Zhu explained.
The researchers' conclusions are based on a series of experiments that showed that removing this sequence from the DNA of cancer cells – both in human cell culture and in mice – leads to shortening of telomeres, aging of cells and the cessation of tumor growth. Subsequently, scientists studied the length of the sequence in DNA samples taken from centenarian Caucasians and African Americans, participants of the Georgia Centenarian Study – a study that was conducted with a group of people aged 100 years and older in the period from 1988 to 2008. The researchers found that the length of the DNA sequence ranged from 53 repeats –or copies –to 160 repeats.
"It varies a lot, and our study actually shows that the telomerase gene is more active in people with a longer sequence," Zhu said.
Since very short sequences were found only in African Americans, the researchers looked more closely at this group and found that centenarians with a short VNTR2-1 sequence were relatively few compared to the control group. However, according to Zhu, it is worth noting that having a short sequence does not necessarily mean that your lifespan will be shorter, as it means that the telomerase gene is less active and the length of your telomeres may be shorter, which may reduce the likelihood of developing cancer.
"Our results suggest that this sequence, VNTR2-1, contributes to the genetic diversity of how we age and how we develop cancer. We know that oncogenes – or cancer genes – and tumor suppressor genes do not explain all the reasons why we get cancer. Our study shows that the picture is much more complicated than the oncogene mutation, and gives good reasons to study the so-called junk DNA more closely," Zhu commented.
Zhu noted that since African Americans have been living in the US for several generations, many of them have Caucasian ancestors from whom they could inherit part of this sequence. Therefore, as a next step, he and his team hope to be able to study the VNTR2-1 sequence in the African population.
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