Telomeres are specific regions of human DNA associated with more than 85% of malignant tumours, and studying them could lead to the development of next-generation anti-cancer drugs with a broad spectrum of activity.

These elements are located at the ends of chromosomes and have a protective function, maintaining the integrity of DNA during cell replication, and play an important role in the cellular ageing process. Each time a cell divides, the telomeres become progressively shorter. When they become too short, the cell loses its ability to replicate properly and may enter an ageing state or die. In cancer cells, an enzyme called telomerase is activated in more than 85% of malignant tumours, making telomeres longer than in normal cells. This gives cancer cells immortality and the ability to reproduce indefinitely. Stabilising G-quadruplexes, the four-stranded helical structures that form in telomeres, with molecules called ligands is an effective approach to inhibiting telomerase activity and limiting the growth of cancer cells. These ligands could then be used as new drugs to treat cancer.

Most current research focuses on G-quadruplexes under ideal conditions, i.e. as biological molecules that do not interact with each other. However, under biologically relevant conditions, such as at the ends of chromosomes, structures composed of several interacting G-quadruplex units, known as multimers, can form.

In a study coordinated by Cristiano De Michele from the Department of Physics at Sapienza, Lucia Comez from the CNR's Officina dei Materiali in Perugia and Alessandro Paciaroni from the Department of Physics and Geology at the University of Perugia, a new method has been developed to obtain information on the stability of telomeric G-quadruplex multimers.

The results of the study, published in the Journal of American Chemical Society (JACS), could be used both to develop next-generation anti-cancer drugs and to evaluate the efficacy of existing ones.

In particular, the researchers first used "extremely coarse-grained" simulations, in which G-quadruplexes are represented by simple geometric shapes such as cylinders or parallelepipeds. These simulations are not particularly heavy and allow the study of thousands of interacting G-quadruplexes, reproducing biologically relevant conditions. This allowed a direct comparison between numerical computer results and experiments performed both in our laboratories and in international research centres, providing a novel representation of G-quadruplex multimers.

"In particular," says De Michele, "we studied how ligands, i.e. potential anti-cancer drugs, act on G-quadruplexes and, thanks to our innovative approach, we were able to understand how they effectively stabilise them.

"In addition," adds Paciaroni, "our work defines a protocol that can be applied to the study of G-quadruplexes, but which can also be used for other biophysical systems in the future.

"This study," concludes Comez, "represents a significant step forward in our journey, which began several years ago, to understand the elusive properties of these highly complex biological systems.

References: 

Stacking Interactions and Flexibility of Human Telomeric Multimers - Benedetta Petra Rosi, Valeria Libera, Luca Bertini, Andrea Orecchini, Silvia Corezzi, Giorgio Schirò, Petra Pernot, Ralf Biehl, Caterina Petrillo, Lucia Comez, Cristiano De Michele, and Alessandro Paciaroni - J. Am. Chem. Soc. 2023 DOI: 10.1021/jacs.3c04810

Further Information

Cristiano De Michele
Department of Physics
cristiano.demichele@uniroma1.it