We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Robustness of DNA Repair through Collective Rate Control.
- Authors
Verbruggen, Paul; Heinemann, Tim; Manders, Erik; von Bornstaedt, Gesa; van Driel, Roel; Höfer, Thomas
- Abstract
DNA repair and other chromatin-associated processes are carried out by enzymatic macromolecular complexes that assemble at specific sites on the chromatin fiber. How the rate of these molecular machineries is regulated by their constituent parts is poorly understood. Here we quantify nucleotide-excision DNA repair in mammalian cells and find that, despite the pathways' molecular complexity, repair effectively obeys slow first-order kinetics. Theoretical analysis and data-based modeling indicate that these kinetics are not due to a singular rate-limiting step. Rather, first-order kinetics emerge from the interplay of rapidly and reversibly assembling repair proteins, stochastically distributing DNA lesion repair over a broad time period. Based on this mechanism, the model predicts that the repair proteins collectively control the repair rate. Exploiting natural cell-to-cell variability, we corroborate this prediction for the lesion-recognition factor XPC and the downstream factor XPA. Our findings provide a rationale for the emergence of slow time scales in chromatin-associated processes from fast molecular steps and suggest that collective rate control might be a widespread mode of robust regulation in DNA repair and transcription.
- Subjects
COMPUTATIONAL biology; MOLECULAR biology; COMPUTER simulation of biological systems; MATHEMATICAL models; PHYSIOLOGICAL control systems; DNA repair; ENZYME regulation; MOLECULAR dynamics; SYSTEMS biology; STOCHASTIC analysis
- Publication
PLoS Computational Biology, 2014, Vol 10, Issue 1, p1
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.1003438