Researchers at the University of Louisville’s James Graham Brown Cancer Center have identified mutations that destabilize a DNA structure that turns a gene off. These mutations occur at four specific sites in what is known as the “hTERT promoter” in more than 75 percent of glioblastomas and melanomas. The research was published recently in the online journal PLOS ONE.
Telomerase is an enzyme largely responsible for the promotion of cell division. Within DNA, telomerase activation is a critical step for human carcinogenesis through the maintenance of telomeres. However, the activation mechanism during carcinogenesis—why cancer gets turned “on”–is not yet wholly understood. What is known is that transcriptional regulation of the human telomerase reverse transcriptase (hTERT) gene is the major mechanism for cancer-specific activation of telomerase. Says study co-author Donald Miller, MD, PhD, “We know that human telomerase is over-expressed in most human cancers, but we’ve never known why.”
In 2013, two studies published in Science and another in Proceedings of the National Academy of Sciences gave the researchers a direction to explore. “These papers said that in most melanomas, mutations existed in the promoter of this telomerase gene. This was the first time that anyone reported common mutations in these promoters,” says Miller.
The Louisville team has shown that the mutations all occur in a region of the hTERT promoter that previously has been shown to form quadruplex DNA. Using a combination of biophysics and molecular modeling, a new form of a quadruplex transcription regulation element is reported. The formation of these quadruplexes in telomeres has been shown to decrease the activity of telomerase.
“We found that the mutations inactivate the gene’s ‘off’ switch so it becomes locked on, destabilizing the quadruplex and allowing it to be over-expressed,” Miller explains. “This over-expression then drives the cells to continue to divide, which is the cause of the cancer.” The researchers will next examine how to unlock the switch from on to off.
Read the article at the PLOS ONE website
