DNA double-strand breaks in and beyond heavy-ion tracks: the role of Base Excision Repair and DNA-damage complexity

Space radiation poses a threat to human health during space missions. Its biological effect largely depends on heavy ions. These induce highly clustered DNA damage along their tracks, thus impacting genomic integrity and cancer risk. δ-electrons induced by fast heavy ions lead to further DNA damage outside ion tracks, which resembles that of sparsely-ionizing radiation.Here we show that repair of DNA base-lesions within heavy-ion tracks causes DNA double-strand breaks (DSBs), which increases difficult to repair in-track DSB clustering. We further found that DSBs induced by δ-electrons of fast heavy ions are more often processed resection-dependent than X-ray-induced DSBs, despite their resemblance. Although δ-electron induced DSBs are frequently resected, their repair is accelerated in G1-phase.These observations imply that the DNA-damage load affects the damage response. Thus, assessing the impact of DNA damage requires more than studying individual lesions or lesion types. Uncovering their interplay is crucial to improve cancer-risk models.