The multiscale distribution of radiation-induced DNA damage and its impact on local genome structure

Li, H.; Xue, T.; McCord, R. P.

doi:10.1101/2025.08.25.672161

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bioRxiv · 10.1101/2025.08.25.672161

The multiscale distribution of radiation-induced DNA damage and its impact on local genome structure

Li, H.·Xue, T.·McCord, R. P.

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Abstract

The three-dimensional genome structure is critical for the regulation of gene expression and repair of DNA damage. While previous work has characterized genome-wide sites of DNA damage caused by etoposide or nucleases, the distribution of double-strand breaks (DSBs) caused by external radiation and how these interact with the 3D genome organization is less well understood. Here, we measure the genomic landscape of radiation-induced DNA damage using END-seq in fibroblasts and lymphoblasts after exposure to 5 Gy X-rays. We identify frequently broken regions and investigate the 3D genome properties around these breaks with Hi-C data. We observe that the distribution of robust breaks correlates with transcriptional and chromatin features of the genome. Transcriptionally active and decondensed regions, such as chromosome 19, the A compartment, and topologically associating domain (TAD) boundaries, show pronounced break probability. We also find evidence of DSB-induced loop formation in the vicinity of frequent radiation-induced breaks. Our data reveal that pre-existing 3D genome architecture influences the distribution of radiation-induced DSBs and that these breaks reshape local chromatin landscapes.

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Li, H., Xue, T., McCord, R. P.. 2025-08-29. The multiscale distribution of radiation-induced DNA damage and its impact on local genome structure. https://doi.org/10.1101/2025.08.25.672161

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