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

Area of Science:

• Space biology
• Molecular biology
• Radiation oncology

Background:

• Cosmic radiation exposure poses significant risks to astronauts, inducing DNA damage that threatens genomic integrity and cell survival.
• DNA double-strand breaks (DSBs) are critical lesions, and their repair pathways (non-homologous end joining and homologous recombination) are tightly regulated.
• Post-translational modifications (PTMs) like phosphorylation and ubiquitylation play key roles in modulating the DNA damage response (DDR).

Purpose of the Study:

• To review the role of PTMs, specifically phosphorylation and ubiquitylation, in regulating DNA repair pathways.
• To identify key proteins involved in the DDR and explore the function of other PTMs like acetylation, methylation, and PARylation.
• To propose novel strategies for developing radioprotectors to mitigate space radiation damage.

Main Methods:

• Literature review focusing on DNA damage response (DDR) pathways and PTMs.
• Analysis of protein involvement in DDR, including specific kinases and ubiquitin ligases.
• Investigation of acetylation, methylation, and PARylation in DNA repair.

Main Results:

• Phosphorylation and ubiquitylation are critical regulators of DSB repair pathway choice.
• Key proteins such as ATM, DNA-PKcs, CtIP, and MDM2 are central to DDR modulation.
• A gap exists in effective radioprotectors, despite research into radiosensitizers.

Conclusions:

• Understanding PTMs in DDR is essential for protecting astronauts from space radiation.
• Future radioprotector development requires integrated strategies like multi-omics, computational methods, and drug repositioning.
• These approaches can facilitate practical applications of radioprotectors for human space exploration.