Never Cared for What They Do: High Structural Stability of Guanine-Quadruplexes in the Presence of Strand-Break Damage

Abstract

DNA integrity is an important factor that assures genome stability and, more generally, the viability of cells and organisms. In the presence of DNA damage, the normal cell cycle is perturbed when cells activate their repair processes. Although efficient, the repair system is not always able to ensure complete restoration of gene integrity. In these cases, mutations not only may occur, but the accumulation of lesions can either lead to carcinogenesis or reach a threshold that induces apoptosis and programmed cell death. Among the different types of DNA lesions, strand breaks produced by ionizing radiation are the most toxic due to the inherent difficultly of repair, which may lead to genomic instability. In this article we show, by using classical molecular simulation techniques, that compared to canonical double-helical B-DNA, guanine-quadruplex (G4) arrangements show remarkable structural stability, even in the presence of two strand breaks. Since G4-DNA is recognized for its regulatory roles in cell senescence and gene expression, including oncogenes, this stability may be related to an evolutionary cellular response aimed at minimizing the effects of ionizing radiation.

Predicting the Three-dimensional Structure of the c-KITOncogene Promoter and the Dynamics of Strongly Coupled Guanine-Quadruplexes

“…[20][21][22][23] Noteworthy, G4s have been shown to be extremely resilient to the inclusion of DNA lesions, including oxidative lesions and abasic sites, and the recruitment of DNA-repair enzymes by damaged G4s has also been associated to epigenetic control. [24][25][26] Despite the extreme importance of the characterization of the proper folding of single G4s from truncated sequences, for instance by X-ray, NMR and electronic circular dichroism (ECD) spectra, 27 this is usually not sufficient to properly infer their behavior in the more complex system represented by DNA. As mentioned, in gene promoter regions G4s are usually coupled in clusters and this complex organization may lead to a welldefined three-dimensional of the individual G4s, which may strongly alter the interaction with their biological partners like helicases or with targeting molecules.…”

“…20–23 Noteworthy, G4s have been shown to be extremely resilient to the inclusion of DNA lesions, including oxidative lesions and abasic sites, and the recruitment of DNA-repair enzymes by damaged G4s has also been associated to epigenetic control. 24–26…”

Predicting the Three-Dimensional Structure of the c-KIT Proto-Oncogene Promoter and the Dynamics of Its Strongly Coupled Guanine Quadruplexes

“…Changes in the central metal ion or the crowding of the medium may induce transitions between parallel and hybrid or antiparallel topologies. − It is noteworthy that G4s are extremely resilient to DNA damage, including oxidative lesions and abasic sites. In this regard, the recruitment of DNA-repair enzymes by damaged G4s has also been associated with epigenetic control, i.e., control involved in regulating gene expression. − …”