An investigation carried out by researchers at the University of Louisville’s James Graham Brown Cancer Center (KY, USA) has defined the role of destabilizing mutations in the human telomerase reverse transcriptase (hTERT) gene promoter that are detectable in >75% of glioblastomas and melanomas. Details of the study appeared recently in PLOS ONE.
Activation of the telomerase enzyme is defined as a critical step for human carcinogenesis, although the activation mechanisms are not currently thoroughly understood. However, transcriptional regulation of the hTERT gene is known to be the major mechanism for cancer-specific activation of telomerase.
Study author Donald Miller (James Graham Brown Cancer Center) commented: “We know that human telomerase is overexpressed in most human cancers, but we’ve never known why.”
Two papers published in 2013 provided the Louisville team with a focus for their research into telomerase in cancer, each reporting that mutations were present in the promoter of the hTERT gene in most melanomas.
Their new study has demonstrated that these mutations occur at four specific sites in a promoter region that has previously been shown to form quadruplex DNA. Harnessing biophysics and molecular modeling techniques, the team uncovered a new form of a quadruplex transcription regulation element. The formation of these quadruplexes in telomeres has been demonstrated to decrease the activity of telomerase.
“We speculated that the occurrence of these mutations could destabilize or alter the recognition of quadruplexes formed by this sequence,” Miller continued. “We found that the mutations inactivate the gene’s ‘off’ switch so it becomes locked on, destabilizing the quadruplex and allowing it to be overexpressed. This overexpression then drives the cells to continue to divide, which is the cause of the cancer.”
Miller described how the team will continue this work, stating: “What we have described in this PLOS ONE article is the on–off switch and provided an entirely new model for that structure. Our next step is to look at how to turn it off that will help lead us to new therapeutics to prevent the occurrence of cancer.”