Robustness of DNA repair through collective rate control.
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.
Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany ; Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
Paul
P
Verbruggen
Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany ; BioQuant Center, Heidelberg, Germany.
Tim
T
Heinemann
Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
Erik
E
Manders
Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany ; BioQuant Center, Heidelberg, Germany.
Gesa
G
von Bornstaedt
Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
Roel
R
van Driel
Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany ; BioQuant Center, Heidelberg, Germany.
Thomas
T
Höfer
D000465:Algorithms; D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D013997:Time Factors; D014158:Transcription, Genetic; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics
C477080:1-(3-dimethylaminopropyl)-3-ethylurea; D002843:Chromatin; D004268:DNA-Binding Proteins; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; D049452:Green Fluorescent Proteins; C086984:XPC protein, human; D014508:Urea; D004247:DNA