title: Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells.
abstract: The concept of DNA "repair centers" and the meaning of radiation-induced foci (RIF) in human cells have remained controversial. RIFs are characterized by the local recruitment of DNA damage sensing proteins such as p53 binding protein (53BP1). Here, we provide strong evidence for the existence of repair centers. We used live imaging and mathematical fitting of RIF kinetics to show that RIF induction rate increases with increasing radiation dose, whereas the rate at which RIFs disappear decreases. We show that multiple DNA double-strand breaks (DSBs) 1 to 2 μm apart can rapidly cluster into repair centers. Correcting mathematically for the dose dependence of induction/resolution rates, we observe an absolute RIF yield that is surprisingly much smaller at higher doses: 15 RIF/Gy after 2 Gy exposure compared to approximately 64 RIF/Gy after 0.1 Gy. Cumulative RIF counts from time lapse of 53BP1-GFP in human breast cells confirmed these results. The standard model currently in use applies a linear scale, extrapolating cancer risk from high doses to low doses of ionizing radiation. However, our discovery of DSB clustering over such large distances casts considerable doubts on the general assumption that risk to ionizing radiation is proportional to dose, and instead provides a mechanism that could more accurately address risk dose dependency of ionizing radiation.
authors.affiliation: Institute of Radiation Protection, German Research Center for Environmental Health (GmbH), Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Neumaier
authors.forename: Joel
authors.initials: J
authors.lastname: Swenson
authors.forename: Christopher
authors.initials: C
authors.lastname: Pham
authors.forename: Aris
authors.initials: A
authors.lastname: Polyzos
authors.forename: Alvin T
authors.initials: AT
authors.lastname: Lo
authors.forename: PoAn
authors.initials: P
authors.lastname: Yang
authors.forename: Jane
authors.initials: J
authors.lastname: Dyball
authors.forename: Aroumougame
authors.initials: A
authors.lastname: Asaithamby
authors.forename: David J
authors.initials: DJ
authors.lastname: Chen
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
authors.forename: Stefan
authors.initials: S
authors.lastname: Thalhammer
authors.forename: Sylvain V
authors.initials: SV
authors.lastname: Costes
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D004260:DNA Repair / Q000502:physiology* / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological; D018570:Risk Assessment; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D049452:Green Fluorescent Proteins