Single-strand break repair pathway disruption impacts radiosensitivity to both low- and high-LET radiation
Abstract
Differences in individual radiosensitivity are not currently reflected in radiotherapy treatment planning, and identifying genetic drivers of this variation is a key step in personalising future treatments. While the role of DNA double-strand break (DSB) repair in radiosensitivity is well-studied, the impacts of single-strand break (SSB) repair defects are relatively unexplored. Through targeted SSB repair gene knockout, we show that disrupted SSB repair increases radiosensitivity, with stronger effects for high Linear Energy Transfer (LET) radiation. Mechanistic studies identified both an increase in DSB production at low LETs, due to delayed SSB repair, and higher levels of unrepaired complex damage at high LETs. This altered sensitivity is also reflected by differences in disease-specific survival for patients with SSB repair gene alterations in a retrospective pan-cancer clinical analysis. SSB repair pathway disruption may therefore be clinically relevant and important to consider for radiotherapy personalisation, particularly for high-LET radiation treatments.
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BibTeX
@article{gardner2026singlestrand,
title = {{Single-strand break repair pathway disruption impacts radiosensitivity to both low- and high-LET radiation}},
author = {Lydia Gardner and Francisco D.C. Guerra Liberal and Shannon Thompson and François Chevalier and Karl Butterworth and Stephen Mcmahon},
journal = {DNA Repair},
year = {2026},
month = oct,
doi = {10.1016/j.dnarep.2026.103968},
url = {https://normandie-univ.hal.science/hal-05830664v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Single-strand break repair pathway disruption impacts radiosensitivity to both low- and high-LET radiation
AU - Lydia Gardner
AU - Francisco D.C. Guerra Liberal
AU - Shannon Thompson
AU - François Chevalier
AU - Karl Butterworth
AU - Stephen Mcmahon
PY - 2026
DA - 2026/10/16
JO - DNA Repair
DO - 10.1016/j.dnarep.2026.103968
UR - https://normandie-univ.hal.science/hal-05830664v1
AB - Differences in individual radiosensitivity are not currently reflected in radiotherapy treatment planning, and identifying genetic drivers of this variation is a key step in personalising future treatments. While the role of DNA double-strand break (DSB) repair in radiosensitivity is well-studied, the impacts of single-strand break (SSB) repair defects are relatively unexplored. Through targeted SSB repair gene knockout, we show that disrupted SSB repair increases radiosensitivity, with stronger effects for high Linear Energy Transfer (LET) radiation. Mechanistic studies identified both an increase in DSB production at low LETs, due to delayed SSB repair, and higher levels of unrepaired complex damage at high LETs. This altered sensitivity is also reflected by differences in disease-specific survival for patients with SSB repair gene alterations in a retrospective pan-cancer clinical analysis. SSB repair pathway disruption may therefore be clinically relevant and important to consider for radiotherapy personalisation, particularly for high-LET radiation treatments.
SN - 1568-7864
SN - 1568-7856
ER -