Simulation par ordinateur et expériences de la sénescence cellulaire radio-induite

Cancer continues to pose a significant challenge to researchers and medical professionals due to its high mortality rates, intricate pathophysiology, and profound impact on public health and quality of life. Among various treatment modalities, radiation therapy is widely employed to target and destroy cancerous cells by inflicting DNA damage. This damage includes single-strand breaks (SSBs), base damage (BD), and double-strand breaks (DSBs), which activate a cascade of cellular pathways leading to cell death. However, radiation therapy also affects surrounding normal cells, as the out-of-field dose radiation often results in a higher accumulation of SSBs in these cells. Consequently, the normal cells may enter a state of senescence (a dormant state) with the potential to transition into secondary cancerous cells under certain conditions.Given this interplay between DNA damage, cellular senescence, and cancer progression, this thesis investigates the molecular and mechanistic aspects of the DNA damage response (DDR) pathway, focusing on the role of SSBs and their repair. By integrating molecular dynamics simulations, mathematical modelling, and experimental validation wherever necessary, this work provides a deeper understanding of DNA repair mechanisms and their implications for cellular senescence and cancer therapy.The main part of this thesis focuses on how the Poly(ADP-ribose)polymerase-1 (PARP1) protein recognizes SSBs. Molecular-scale simulations are employed to analyze PARP1's interaction with a hairpin DNA fragment containing an SSB, offering novel insights into the early steps of the single-strand break repair (SSBR) pathway. Building on this foundation, the study further explores the structural and mechanical effects of SSBs and DSBs within dinucleosome with varying linker DNA lengths. These investigations reveal how different types of DNA damage induce conformational changes in chromatin structure, facilitating the recruitment of DDR proteins to damage sites.The final part of the thesis transitions to a macroscopic perspective, modelling the SSBR pathway to understand cellular responses to DNA damage. The study analyses cell fate decisions under varying damage conditions using Michaelis-Menten kinetics. Additionally, GEANT4-TOPAS Monte Carlo simulations are employed to study radiation-induced DNA damage, quantifying the different type of DNA damages induced during radiation treatment. These models are further integrated into the DaMaRiS (DNA Mechanistic Repair Simulator) framework, to model the SSBR pathway to simulate DNA repair dynamics comprehensively.This multidisciplinary approach, combining computational simulations, mathematical modelling, and experimental insights, advances our understanding of DNA repair mechanisms.Keywords: Single-strand breaks, Senescence, PARP1, Molecular dynamic simulations, Monte-Carlo simulations.