Junk DNA Sequence a Likely Driver of Telomerase Gene Activity

Junk DNA Sequence a Likely Driver of Telomerase Gene Activity
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A DNA region known as VNTR2-1 appears to drive the activity of the telomerase gene, according to research by a team headed by Jiyue Zhu, a professor in the College of Pharmacy and Pharmaceutical Sciences, Washington State University. The study was published in the journal Proceedings of the National Academy of Sciences (PNAS).

Zhu said that his team’s latest finding is especially notable because of the type of DNA sequence involved.

“Almost 50% of our genome consists of repetitive DNA that does not code for protein,” Zhu said. “These DNA sequences tend to be considered as ‘junk DNA’ or dark matters in our genome, and they are difficult to study. Our study describes that one of those units actually has a function in that it enhances the activity of the telomerase gene.”

VNTR2-1 is an enhancer-like element, consisting of 42-bp repeats with an array of enhancer boxes. Zhu’s team found it cooperated with the proximal promoter in the regulation of hTERT transcription by basic helix–loop–helix transcription factors and maintained hTERT expression during embryonic stem-cell differentiation. Multiple independent sequence variants of the hTERT locus have been associated with telomere length and cancer risks in genome-wide association studies.

In normal cells, the length of telomeres gets a little bit shorter every time cells duplicate their DNA before they divide. When telomeres get too short, cells can no longer reproduce, causing them to age and die. However, in certain cell types—including reproductive cells and cancer cells—the activity of the telomerase gene ensures that telomeres are reset to the same length when DNA is copied. This restarts the aging clock in new offspring and explains why cancer cells can continue to multiply and form tumors.

Zhu’s team’s finding is based on experiments that found that deleting VNTR2-1 from cancer cells—both in a human cell line and in mice—caused telomeres to shorten, cells to age, and tumors to stop growing. Subsequently, they looked at the length of the sequence in DNA samples taken from Caucasian and African American centenarians and control participants in the Georgia Centenarian Study, a study that followed a group of people aged 100 or above between 1988 and 2008. The researchers found that the length of the sequence ranged from as short as 53 repeats—or copies—of the DNA to as long as 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 American participants, they looked more closely at that group and found that there were relatively few centenarians with a short VNTR2-1 sequence as compared to control participants. However, Zhu said it was worth noting that having a shorter sequence does not necessarily mean your lifespan will be shorter, because it means the telomerase gene is less active and your telomere length may be shorter, which could make you less likely to develop cancer.

“Our findings are telling us that this VNTR2-1 sequence contributes to the genetic diversity of how we age and how we get cancer,” Zhu said. “We know that oncogenes—or cancer genes—and tumor suppressor genes don’t account for all the reasons why we get cancer. Our research shows that the picture is a lot more complicated than a mutation of an oncogene and makes a strong case for expanding our research to look more closely at this so-called junk DNA.”

Zhu noted that since African Americans have been in the United States for generations, many of them have Caucasian ancestors from whom they may have inherited some of this sequence. So as a next step, he and his team hope to be able to study the sequence in an African population.