Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells

Teresa Neumaier, Joel Swenson, Christopher Pham, Aris Polyzos, Alvin T. Lo, PoAn Yang, Jane Dyball, Aroumougame Asaithamby, David J. Chen, Mina J. Bissell, Stefan Thalhammer, Sylvain V. Costes

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Abstract

The concept of DNA "repair centers" and the meaning of radiationinduced 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.

Original languageEnglish (US)
Pages (from-to)443-448
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number2
DOIs
StatePublished - Jan 10 2012

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Neumaier, T., Swenson, J., Pham, C., Polyzos, A., Lo, A. T., Yang, P., Dyball, J., Asaithamby, A., Chen, D. J., Bissell, M. J., Thalhammer, S., & Costes, S. V. (2012). Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells. Proceedings of the National Academy of Sciences of the United States of America, 109(2), 443-448. https://doi.org/10.1073/pnas.1117849108