New Conceptual Interpretations of Mechanisms for the Repair of Double-Strand DNA Breaks and Their Mathematical Modeling Bondarenko M.A.1,*, Knigavko V.G.1, Zaytseva O.V.1, Nikonov A. Yu.2, Kovalenko G.A.2 1Department of Medical and Biological Physics and Medical Information Science, Kharkiv National Medical University, Kharkiv, Ukraine 2Department of Prosthetic Dentistry, Kharkiv Medical Academy of Postgraduate Education, Kharkiv, Ukraine *Corresponding Author E-mail: bondaren.koma3007@gmail.com
Online published on 24 February, 2020. Abstract The genetic apparatus of the cell is exposed to a serious risk of damage under the constant influence of endogenous and exogenous factors. One of the most complex damage for repair is double-strand DNA breaks and DNA-protein cross-links, leading to various types of mutations and chromosomal rearrangements that can induce genome instability, carcinogenesis, or the start of the cell apoptosis process. Nevertheless, numerous data from studies of DNA repair pathways do not provide the final pattern of the repair of double-strand DNA breaks and DNA-protein cross-links, as well as any mathematical model for calculating the survival of cells irradiated by photon radiation at various stages of the cell cycle. According to our assumptions, during the repair of double-strand breaks, damaged DNA segments are cut out from both sides at the boundaries of the entire damaged loop domain (replicon). The degradation of the damaged strand has an analogy with the mechanism of apoptosis, because during chromatin degradation, as during apoptosis, DNA is destructurized to the level of nucleosomes, followed by their “use” by the cell. As for the repair of DNA-protein cross-links, they are one of the stages of the multi-stage hierarchy of the repair pathways of double-strand DNA breaks. Apparently, in some cases, the repair of double-strand DNA breaks requires the creation of additional protein structures by the cell, which spatially fix the damaged DNA segment of the cell during repair. The creation of these structures requires additional time and additional protein synthesis. After repair, this additional protein is completely detached from the sites that define the boundaries of those cell structures that participated in the repair process. A mathematical model has been proposed for estimating the probability of the repair of double-strand DNA breaks depending on the stage of the cell cycle and on the value of the absorbed dose, as well as the probability of survival of the irradiated cells for different durations of the repair interval. The article shows the possibility of calculating the probability that the cell at the time of irradiation is at such a stage of the cell cycle, at which repair is either impossible, or the time required for the repair of one doublestrand break is not sufficient. The study calculates the probability of cell survival at different stages of the cell cycle, when it is possible to repair one double-strand break, no more than two double-strand breaks, and, in general, n units of double-strand breaks. Top Keywords Double-Strand DNA Breaks, DNA-Protein Cross-Links, Repair Mechanisms, Mathematical Probabilistic Modeling. Top |