Work

Differential roles of DNA double strand break repair pathways in response to X-ray, proton, and alpha-particle irradiation

Year: 2025

Type: article

Abstract: PURPOSE: High linear energy transfer (LET) radiation is more harmful than low LET radiation because it deposits energy in a concentrated manner, resulting in clustered DNA damage (CDD). Double strand breaks (DSBs) are among the most damaging types of DNA damage, and if not repaired, they may trigger cell death. DSBs can be repaired through three mechanisms: non-homologous end joining (NHEJ), homologous recombination (HR), and theta-mediated end joining (TMEJ). This study aimed to assess how these pathways contribute to repairing DSBs induced by low LET X-ray and proton radiation, and high LET alpha-particle radiation. MATERIALS AND METHODS: We used mouse embryonic stem (mES) cells lacking key repair proteins to examine clonogenic survival and the formation and resolution of 53BP1 foci, a DNA damage marker, after exposure to X-ray, proton, and alpha-particle radiation. RESULTS AND CONCLUSIONS: The results showed increased sensitivity to X-ray and proton radiation in NHEJ, HR, and TMEJ repair-deficient cell lines compared to wild-type cells, with similar trends for both radiation types. Notably, Rad54-deficient cells showed slower resolution of 53BP1 foci after proton exposure, indicating increased reliance on HR for repairing proton-induced DSBs. Clonogenic survival assays revealed a relative biological effectiveness (RBE) of 4.6-5.8 for alpha-particles compared to protons and X-rays, confirming that alpha-particles are more effective at causing cell death. Our findings suggest that TMEJ is important for repairing DSBs caused by alpha-particles. This study highlights differences in repairing low LET versus high LET DNA damage, offering new insights for radiation biology and therapeutic strategies.

Source: International Journal of Radiation Biology

DOI: 10.1080/09553002.2025.2590742

Authors: Gerarda van de Kamp, Tim Heemskerk, Marta Rovituso, Roland Kanaar, Jeroen Essers

Institutions: Erasmus MC, Oncode Institute, Erasmus MC Cancer Institute, Holland Particle Therapy Center

Language: English

Topic: DNA Repair Mechanisms

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: Varian Medical Systems, KWF Kankerbestrijding, Oncode Institute