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Issue 7, 2014
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Experimental design, validation and computational modeling uncover DNA damage sensing by DNA-PK and ATM

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Abstract

Reliable and efficient detection of DNA damage constitutes a vital capability of human cells to maintain genome stability. Following DNA damage, the histone variant H2AX becomes rapidly phosphorylated by the DNA damage response kinases DNA-PKcs and ATM. H2AX phosphorylation plays a central role in signal amplification leading to chromatin remodeling and DNA repair initiation. The contribution of DNA-PKcs and ATM to H2AX phosphorylation is however puzzling. Although ATM is required, DNA-PKcs can substitute for it. Here we analyze the interplay between DNA-PKcs and ATM with a computational model derived by an iterative workflow: switching between experimental design, experiment and model analysis, we generated an extensive set of time-resolved data and identified a conclusive dynamic signaling model out of several alternatives. Our work shows that DNA-PKcs and ATM enforce a biphasic H2AX phosphorylation. DNA-PKcs can be associated to the initial, and ATM to the succeeding phosphorylation phase of H2AX resulting into a signal persistence detection function for reliable damage sensing. Further, our model predictions emphasize that DNA-PKcs inhibition significantly delays H2AX phosphorylation and associated DNA repair initiation.

Graphical abstract: Experimental design, validation and computational modeling uncover DNA damage sensing by DNA-PK and ATM

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Publication details

The article was received on 17 Feb 2014, accepted on 04 May 2014 and first published on 09 May 2014


Article type: Paper
DOI: 10.1039/C4MB00093E
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Mol. BioSyst., 2014,10, 1978-1986
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    Experimental design, validation and computational modeling uncover DNA damage sensing by DNA-PK and ATM

    R. J. Flassig, G. Maubach, C. Täger, K. Sundmacher and M. Naumann, Mol. BioSyst., 2014, 10, 1978
    DOI: 10.1039/C4MB00093E

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