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| Home > Publications database > Evidence for Quasi-High-LET Biological Effects in Clinical Proton Beams That Suppress c-NHEJ and Enhance HR and Alt-EJ. |
| Home > Publications database > Evidence for Quasi-High-LET Biological Effects in Clinical Proton Beams That Suppress c-NHEJ and Enhance HR and Alt-EJ. |
| Journal Article | DKFZ-2026-00082 |
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2026
MDPI
Basel
Abstract: Protons are conventionally regarded as a low-linear energy transfer (low-LET) radiation modality with a relative biological effectiveness (RBE) of 1.1, suggesting direct mechanistic similarity to X-rays in the underpinning biological effects. However, exposure to spread-out Bragg peak (SOBP) protons reveals instructive deviations from this assumption. Indeed, proton beams have a maximum LET of ~5 keV/µm but display reduced reliance on classical non-homologous end joining (c-NHEJ) as well as an increased dependence on homologous recombination (HR) and alternative end joining (alt-EJ). These features are well described in cells exposed to high-LET radiation and typically manifest between 100 and 150 keV/µm. We hypothesized that this apparent discrepancy reflects biological consequences of proton-beam properties that remain uncharacterized. In the present study, we outline exploratory experiments aiming at uncovering such mechanisms. We begin by investigating for both entrance and SOBP protons the dose-dependent engagement of HR we recently showed for X-rays. Consistent with our previous findings with X-rays, HR engagement after exposure to both types of proton beams declined with dose, from ~80% at 0.2 Gy to less than 20% at higher doses. RAD51/γH2AX foci ratios, reflecting HR engagement, were modestly higher following proton irradiation, in line with increased HR utilization. G2-checkpoint activation, previously linked to HR, was also stronger after exposure to protons, as was DNA end resection. Moreover, the formation of structural chromosomal abnormalities (SCAs) was higher for SOBP than entrance protons and X-rays. Collectively, our results suggest quasi-high-LET characteristics for proton beams and raise the question as to the physical proton properties that underpin them. We discuss that the commonly employed definition of LET may be insufficient for this purpose.
Keyword(s): Linear Energy Transfer (MeSH) ; Humans (MeSH) ; DNA End-Joining Repair: radiation effects (MeSH) ; Protons (MeSH) ; Homologous Recombination: radiation effects (MeSH) ; Proton Therapy (MeSH) ; Dose-Response Relationship, Radiation (MeSH) ; X-Rays (MeSH) ; DNA double strand breaks (DSBs) ; alternative end joining (alt-EJ) ; classical non-homologous end joining (c-NHEJ) ; homologous recombination (HR) ; ionizing radiation (IR) ; linear energy transfer (LET) ; proton radiation ; relative biological effectiveness (RBE) ; structural chromosomal abnormalities (SCAs) ; Protons
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