Issue 7, 2014

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

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

Supplementary files

Article information

Article type
Paper
Submitted
17 Feb 2014
Accepted
04 May 2014
First published
09 May 2014
This article is Open Access
Creative Commons BY license

Mol. BioSyst., 2014,10, 1978-1986

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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