Scientists Discover the Role of Gene Mutations Involved in 75% of Glioblastomas and Melanomas
After initiating several biophysical computational studies, researchers have identified mutations that destabilize a DNA structure that turns a gene “off.” They found that these mutations occur at four specific sites in the human telomerase reverse transcriptase (hTERT) promoter in over 75% of glioblastomas and melanomas. The finding, reported by Chaires et al in PLoS One, could lead to new therapeutics that target the hTERT gene.
Study Methodology and Findings
The researchers used a combination of biophysics and molecular modeling to show that the hTERT mutation promoter sequence forms a novel G-quadruplex structure consisting of three contiguous, stacked parallel quadruplexes. The hTERT mutations map to the central quadruplex within this structure, and lead to an alteration of its hydrodynamic properties and stability. The formation of these quadruplexes in telomeres has been shown to decrease the activity of telomerase.
According to the study abstract, “More than 90% of human tumors overexpress telomerase, as do rapidly dividing cells, such as stem cells and germ cells. The mechanism by which hTERT expression is dysregulated has been largely unknown.
The data presented here indicate that the common mutations in the hTERT promoter occur in a quadruplex structure in this region. It is possible by altering recognition elements and stability of this region, that the ‘transcriptionally active’ duplex DNA structure with the ETS binding site would be favored.”
Targeting hTERT
“Because of its ubiquitous overexpression and its critical role in almost all tumors, telomerase is an excellent therapeutic target,” wrote the study authors. “The concept of reversing promoter silencing via mutations that cause quadruplex destabilization is an exciting new paradigm and provides the first plausible rationalization of mutation mediated gene transcription by quadruplex control.”
Jonathan B. Chaires, PhD, of the University of Louisville, Kentucky, is the corresponding author for the PLoS One article.
Funding for this study was supported by grants from the National Institutes of Health and the James Graham Brown Foundation. The authors reported no conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
