Modeling of DNA Damage Repair and Cell Response in Relation to p53 System Exposed to Ionizing Radiation

Abstract

Repair of DNA damage induced by ionizing radiation plays an important role in the cell response to ionizing radiation. Radiation-induced DNA damage also activates the p53 system, which determines the fate of cells. The kinetics of repair, which is affected by the cell itself and the complexity of DNA damage, influences the cell response and fate via affecting the p53 system. To mechanistically study the influences of the cell response to different LET radiations, we introduce a new repair module and a p53 system model with NASIC, a Monte Carlo track structure code. The factors determining the kinetics of the double-strand break (DSB) repair are modeled, including the chromosome environment and complexity of DSB. The kinetics of DSB repair is modeled considering the resection-dependent and resection-independent compartments. The p53 system is modeled by simulating the interactions among genes and proteins. With this model, the cell responses to low- and high-LET irradiation are simulated, respectively. It is found that the kinetics of DSB repair greatly affects the cell fate and later biological effects. A large number of DSBs and a slow repair process lead to severe biological consequences. High-LET radiation induces more complex DSBs, which can be repaired by slow processes, subsequently resulting in a longer cycle arrest and, furthermore, apoptosis and more secreting of TGFβ. The Monte Carlo track structure simulation with a more realistic repair module and the p53 system model developed in this study can expand the functions of the NASIC code in simulating mechanical radiobiological effects.

Drug Discovery Targeting Post-Translational Modifications in Response to DNA Damages Induced by Space Radiation

“…Crucially, increased cancer risks have been extensively reported [2,7,8]. Ionizing radiation exposure leads to chromosomal aberrations [9], DNA damage [10,11], alterations in the cell cycle [12,13], and apoptosis [14,15]. However, the complex nature and small astronaut cohort have made the research on space radiation protection challenging and the results highly uncertain [16].…”

The DNA damage response to radiological imaging: from ROS and γH2AX foci induction to gene expression responses in vivo

“…Early on in the DDR cascade, serine 139 of histone H2AX (γH2AX) is phosphorylated, which signals the presence of DNA double strand breaks (DSBs) (Rogakou et al 1998), one of the most deleterious DNA lesions (Schipler and Iliakis 2013). Downstream, a complex network of pro-survival or pro-death genes, usually p53-controlled (Hu et al 2022), interact to determine the cellular fate ( (Valdiglesias et al 2013). The application of gene expression pro les in epidemiological studies has so far been limited by their transient nature (Hall et al 2017).…”

The DNA damage response to radiological imaging: from ROS and γH2AX foci induction to gene expression responses in vivo

“…Early on in the DDR cascade, serine 139 of histone H2AX (γH2AX) is phosphorylated, which signals the presence of DNA double-strand breaks (DSBs) (Rogakou et al 1998 ), one of the most deleterious DNA lesions (Schipler and Iliakis 2013 ). Downstream, a complex network of pro-survival or pro-death genes, usually p53-controlled (Hu et al 2022 ), interact to determine the cellular fate (Christmann and Kaina 2013 ; Roos et al 2016 ) both after environmentally-relevant (Amundson et al 2000 ; Sokolov and Neumann 2015 ) and high doses (Beer et al 2014 ; El-Saghire et al 2013 ). Exploiting these molecular changes and the cytogenetic end-products that may follow IR exposure, a range of IR biomarkers have been proposed for use in biodosimetry (Swartz et al 2010 ) or epidemiological studies (Hall et al 2017 ; Pernot et al 2012 ).…”