DNA damage response - implications for radiosensitivity prediction

Abstract (English)

Endogenous DNA damage (DDR) arises from normal cellular processes, primarily through the reactive oxygen species (ROS), which can cause oxidative modifications to DNA bases, such as 8-oxo-7,8-dihydroguanine. Furthermore, errors during DNA replication can introduce mutations if not repaired. Exogenous damage results from external factors, for example ultraviolet radiation induces direct damage by forming cyclobutane pyrimidine dimers, which distort DNA structure and hinder replication. Ionizing radiation leads to single-strand breaks (SSBs) and double-strand breaks (DSBs), both of which are detrimental. Various chemicals, such as polycyclic aromatic hydrocarbons can interact with DNA, causing alkylation or the formation of bulky adducts that disrupt normal functions. DNA damage response (DDR) is a critical cellular mechanism that detects and repairs DNA lesions to maintain genomic stability. The key components of a DDR include sensors, transducers, and effectors. Sensors, such as Ataxia Telangiectasia Mutated (ATM) and ATR (ATM and Rad3-related) are activated in response to DDR, particularly DSBs and replication stress. These sensors initiate signaling cascades that involve transducers, such as CHK1 and CHK2, which relay the damage signal to downstream effectors. Effectors, such as p53 and BRCA1/2, play pivotal roles in regulating cell cycle checkpoints, apoptosis, and the activation of DNA repair pathways. The DDR encompasses several key repair pathways: homologous recombination repairs DSBs using a homologous template, ensuring high-fidelity repair; non-homologous end joining directly ligates broken DNA ends without a template, which can introduce mutations; base excision repair (BER) corrects small base lesions caused by oxidative damage; and nucleotide excision repair (NER) removes bulky DNA adducts that distort the helix. Each of these pathways is activated depending on the type of damage encountered, highlighting the complexity and specificity of DDR. Understanding the intricate mechanisms of DDR, not only sheds light on fundamental cellular processes, but also has significant implications for cancer therapy, particularly in developing targeted treatments that exploit deficiencies in DNA repair mechanisms. Defects in DDR mechanisms can lead to increased radiosensitivity, as observed in conditions such as ataxia-telangiectasia and Nijmegen breakage syndrome, where mutations in key DDR genes impair the repair of radiation-induced lesions. Biomarkers associated with DDR, such as γ-H2AX and RAD51, are valuable tools for assessing radiosensitivity. These markers reflect the extent of DDR and the effectiveness of repair processes, providing insights into individual patient responses to radiation therapy. Genetic mutations and polymorphisms affecting DDR proteins further contribute to the variability in radiosensitivity among patients, highlighting the need for personalized treatment approaches. Current predictive models for radiosensitivity integrate these DDR-related biomarkers to improve the accuracy of treatment outcome prognosis. By combining genomic data with clinical parameters, researchers have aimed to develop robust models that can predict patient-specific responses to radiotherapy. The integration of biomarkers into these predictive frameworks enhances their utility, allowing better stratification of patients based on their radiosensitivity profiles.