Post-translational modification networks in radiation-induced DNA damage repair: from mechanistic crosstalk to radiosensitization strategies

Radiotherapy (RT) is a cornerstone of cancer treatment, but intrinsic and acquired radioresistance remain major barriers to the therapeutic efficacy of RT. The capacity of tumor cells to repair radiation-induced DNA damage is a major determinant of treatment response. Post-translational modifications (PTMs) constitute a dynamic regulatory layer of the DNA damage response, influencing damage sensing, chromatin remodeling, repair-factor stability and recruitment, and repair pathway choice. This review examines how interacting PTMs regulate key repair nodes in homologous recombination (HR), canonical non-homologous end joining (c-NHEJ), alternative end joining (alt-EJ), base excision repair/single-strand break repair (BER/SSBR), and the Fanconi anemia (FA) pathway, with particular emphasis on multilayered PTM regulation of individual repair proteins and PTM crosstalk between different repair factors. We further compare PTM regulation of shared repair nodes in tumor and normal cells or tissues and discuss how differential dependence on common repair programs may influence therapeutic selectivity. Finally, PTM-targeted radiosensitization is evaluated in the context of the tumor–normal therapeutic window, with explicit distinction between active normal-tissue protection, preserved normal-tissue tolerance, and treatment-associated toxicity. Collectively, current evidence suggests the possibility of preferentially disrupting tumor DNA repair while limiting normal-tissue injury in selected settings.