%0 Journal Article
%A Mladenov, Emil
%A Pressler, Mina
%A Mladenova, Veronika
%A Soni, Aashish
%A Li, Fanghua
%A Heinzelmann, Feline
%A Esser, Johannes Niklas
%A Hessenow, Razan
%A Gkika, Eleni
%A Jendrossek, Verena
%A Timmermann, Beate
%A Stuschke, Martin
%A Iliakis, George
%T Evidence for Quasi-High-LET Biological Effects in Clinical Proton Beams That Suppress c-NHEJ and Enhance HR and Alt-EJ.
%J Cells
%V 15
%N 1
%@ 2073-4409
%C Basel
%I MDPI
%M DKFZ-2026-00082
%P 86
%D 2026
%Z #DKTKZFB26#
%X 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
%K Linear Energy Transfer
%K Humans
%K DNA End-Joining Repair: radiation effects
%K Protons
%K Homologous Recombination: radiation effects
%K Proton Therapy
%K Dose-Response Relationship, Radiation
%K X-Rays
%K DNA double strand breaks (DSBs) (Other)
%K alternative end joining (alt-EJ) (Other)
%K classical non-homologous end joining (c-NHEJ) (Other)
%K homologous recombination (HR) (Other)
%K ionizing radiation (IR) (Other)
%K linear energy transfer (LET) (Other)
%K proton radiation (Other)
%K relative biological effectiveness (RBE) (Other)
%K structural chromosomal abnormalities (SCAs) (Other)
%K Protons (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41511369
%2 pmc:PMC12785619
%R 10.3390/cells15010086
%U https://inrepo02.dkfz.de/record/307610