% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Mladenov:307610,
      author       = {E. Mladenov and M. Pressler and V. Mladenova and A. Soni
                      and F. Li and F. Heinzelmann and J. N. Esser and R. Hessenow
                      and E. Gkika and V. Jendrossek$^*$ and B. Timmermann and M.
                      Stuschke$^*$ and G. Iliakis},
      title        = {{E}vidence for {Q}uasi-{H}igh-{LET} {B}iological {E}ffects
                      in {C}linical {P}roton {B}eams {T}hat {S}uppress c-{NHEJ}
                      and {E}nhance {HR} and {A}lt-{EJ}.},
      journal      = {Cells},
      volume       = {15},
      number       = {1},
      issn         = {2073-4409},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2026-00082},
      pages        = {86},
      year         = {2026},
      note         = {#DKTKZFB26#},
      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.},
      keywords     = {Linear Energy Transfer / Humans / DNA End-Joining Repair:
                      radiation effects / Protons / Homologous Recombination:
                      radiation effects / Proton Therapy / Dose-Response
                      Relationship, Radiation / X-Rays / DNA double strand breaks
                      (DSBs) (Other) / alternative end joining (alt-EJ) (Other) /
                      classical non-homologous end joining (c-NHEJ) (Other) /
                      homologous recombination (HR) (Other) / ionizing radiation
                      (IR) (Other) / linear energy transfer (LET) (Other) / proton
                      radiation (Other) / relative biological effectiveness (RBE)
                      (Other) / structural chromosomal abnormalities (SCAs)
                      (Other) / Protons (NLM Chemicals)},
      cin          = {ED01},
      ddc          = {570},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41511369},
      pmc          = {pmc:PMC12785619},
      doi          = {10.3390/cells15010086},
      url          = {https://inrepo02.dkfz.de/record/307610},
}