title: Visualisation of γH2AX foci caused by heavy ion particle traversal; distinction between core track versus non-track damage.
abstract: Heavy particle irradiation produces complex DNA double strand breaks (DSBs) which can arise from primary ionisation events within the particle trajectory. Additionally, secondary electrons, termed delta-electrons, which have a range of distributions can create low linear energy transfer (LET) damage within but also distant from the track. DNA damage by delta-electrons distant from the track has not previously been carefully characterised. Using imaging with deconvolution, we show that at 8 hours after exposure to Fe (∼200 keV/µm) ions, γH2AX foci forming at DSBs within the particle track are large and encompass multiple smaller and closely localised foci, which we designate as clustered γH2AX foci. These foci are repaired with slow kinetics by DNA non-homologous end-joining (NHEJ) in G1 phase with the magnitude of complexity diminishing with time. These clustered foci (containing 10 or more individual foci) represent a signature of DSBs caused by high LET heavy particle radiation. We also identified simple γH2AX foci distant from the track, which resemble those arising after X-ray exposure, which we attribute to low LET delta-electron induced DSBs. They are rapidly repaired by NHEJ. Clustered γH2AX foci induced by heavy particle radiation cause prolonged checkpoint arrest compared to simple γH2AX foci following X-irradiation. However, mitotic entry was observed when ∼10 clustered foci remain. Thus, cells can progress into mitosis with multiple clusters of DSBs following the traversal of a heavy particle.
authors: Research Center for Charged Particle Therapy and International Open Laboratory, National Institute of Radiological Sciences, Chiba, Japan.
authors: Nakako Izumi
authors: NI
authors: Nakajima
authors: Holly
authors: H
authors: Brunton
authors: Ritsuko
authors: R
authors: Watanabe
authors: Amruta
authors: A
authors: Shrikhande
authors: Ryoichi
authors: R
authors: Hirayama
authors: Naruhiro
authors: N
authors: Matsufuji
authors: Akira
authors: A
authors: Fujimori
authors: Takeshi
authors: T
authors: Murakami
authors: Ryuichi
authors: R
authors: Okayasu
authors: Penny
authors: P
authors: Jeggo
authors: Atsushi
authors: A
authors: Shibata
mesh_terms: D002460:Cell Line; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004249:DNA Damage; D020450:Heavy Ions / Q000009:adverse effects*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000009:adverse effects*; D018499:Linear Energy Transfer; D008853:Microscopy; D008938:Mitosis / Q000528:radiation effects; D057054:Molecular Imaging
chemical_list: C468783:H2AX protein, human; D006657:Histones; D007501:Iron
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