Cancer is caused by changes in DNA sequences (genes) and subsequently, the function of their end product, proteins. In a recent study, a team of researchers proposed to use the architecture of a specific DNA to control the synthesis of the protein factor, as to regulate the progression of some cancers, especially lung, breast, and glioblastoma (brain tumour).
The cancer genes and proteins are called oncogenes and oncoproteins. Epidermal Growth Factor Receptor (EGFR) protein is involved in cell signaling pathways that control cell division and survival. One such important gene that codes for EGFR protein is found to be involved in many cancers.
“EGFR protein is necessary for normal cell growth, division, and propagation. However, mutations in the gene and overproduction of the protein that elevate the activity of this signalling pathway cause the progression of lung, breast, and glioblastoma cancers,” explains Dr S.G. Srivatsan, the lead researcher.
DNA adopts many forms which serve as natural regulators of protein expression. One such architecture is a G-quadruplex, which is formed by genes that have multiple stretches of guanosine nucleosides. G-quadruplex structures act like “speed breakers” and regulate protein synthesis, something like controlling the flow of traffic.
The functional region of the EGFR gene harbours a unique structural motif composed of a G-quadruplex and a hairpin structure placed side-by-side. The researchers propose that this architecture could be used to control the synthesis of the protein factor. They believe that targeting non-canonical nucleic acid structural elements that act as natural regulators could be a viable approach to control EGFR production.
“This could be potentially achieved by developing drug-like compounds that bind simultaneously to G-quadruplex and hairpin parts, and stabilize the architecture. This way, one could reduce the overproduction of the protein and maintain normal function of it in the cells,” the researchers observe.
“My student Saddam Khatik developed a new probe system that reports different structures of DNA, particularly of G-quadruplexes. As the DNA is a string of Adenosine, Guanosine, Thymidine, and Cytidine nucleosides, we prepared a labelled nucleoside. Our probe serves like a CCTV camera, but the difference is that it gives information on the structure in the form of fluorescence and Nuclear Magnetic Resonance (NMR) signals,” Dr Srivatsan informs.
When introduced into the EGFR DNA, the probe gives unique spectral (fluorescence and NMR) signatures for the G-quadruplex-hairpin architectures. Using these signatures, the researchers were able to study the structural diversity, dynamics, and interaction with small molecule binders in a cell model (Frog eggs).
The team performed replication experiments in the absence and presence of small molecule binders. The experiments revealed that the replication efficiency could be controlled by using G-quadruplex binders.
The results validated that EGFR G-quadruplex forming domain represents a new point of intervention to decrease the oncogenic activity of EGFR. The researchers underline the further requirement of developing small molecule binders that simultaneously target both G-quadruplex and hairpin domains for enhanced selectivity and druggability.
The study team comprised researchers Saddam Y. Khatik, Sruthi Sudhakar, Satyajit Mishra, Jeet Kalia, P.I. Pradeepkumar, and S.G. Srivatsan from the Indian Institute of Science Education and Research (IISER), Pune and Bhopal, and the Indian Institute of Technology Bombay (IITB). The study has been published in The Chemical Science. The work was supported by India Alliance and Science and Engineering Research Board (SERB) grants.
India Science Wire
