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

Abstract

DNA damage in astronauts induced by cosmic radiation poses a major barrier to human space exploration. Cellular responses and repair of the most lethal DNA double-strand breaks (DSBs) are crucial for genomic integrity and cell survival. Post-translational modifications (PTMs), including phosphorylation, ubiquitylation, and SUMOylation, are among the regulatory factors modulating a delicate balance and choice between predominant DSB repair pathways, such as non-homologous end joining (NHEJ) and homologous recombination (HR). In this review, we focused on the engagement of proteins in the DNA damage response (DDR) modulated by phosphorylation and ubiquitylation, including ATM, DNA-PKcs, CtIP, MDM2, and ubiquitin ligases. The involvement and function of acetylation, methylation, PARylation, and their essential proteins were also investigated, providing a repository of candidate targets for DDR regulators. However, there is a lack of radioprotectors in spite of their consideration in the discovery of radiosensitizers. We proposed new perspectives for the research and development of future agents against space radiation by the systematic integration and utilization of evolutionary strategies, including multi-omics analyses, rational computing methods, drug repositioning, and combinations of drugs and targets, which may facilitate the use of radioprotectors in practical applications in human space exploration to combat fatal radiation hazards.

Does Selection for Longevity in Acheta domesticus Involve Sirtuin Activity Modulation and Differential Response to Activators (Resveratrol and Nanodiamonds)?

“…Considering that DSBs are known to be cytotoxic, the observed reduction in their occurrence due to the tested substances implies potential therapeutic effects. However, the unexpected increase in DSBs after RV treatment in the H strain on day 15 indicates a dual role of RV in modulating DNA damage, possibly influenced by strain-dependent factors [40].…”

“…ATM is a major regulator of DNA repair mechanisms, particularly in situations involving severe DNA damage, such as double-strand breaks. This phenomenon is critical to understanding how cells respond to such damage and initiate repair processes [40].…”