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-exci...

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Autores principales:	Paul Verbruggen, Tim Heinemann, Erik Manders, Gesa von Bornstaedt, Roel van Driel, Thomas Höfer
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/76adebf17d254242a219f3d3304d1c38
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spelling	oai:doaj.org-article:76adebf17d254242a219f3d3304d1c382021-11-18T05:53:11ZRobustness of DNA repair through collective rate control.1553-734X1553-735810.1371/journal.pcbi.1003438https://doaj.org/article/76adebf17d254242a219f3d3304d1c382014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24499930/pdf/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358DNA 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.Paul VerbruggenTim HeinemannErik MandersGesa von BornstaedtRoel van DrielThomas HöferPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 10, Iss 1, p e1003438 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Paul Verbruggen Tim Heinemann Erik Manders Gesa von Bornstaedt Roel van Driel Thomas Höfer Robustness of DNA repair through collective rate control.
description	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.
format	article
author	Paul Verbruggen Tim Heinemann Erik Manders Gesa von Bornstaedt Roel van Driel Thomas Höfer
author_facet	Paul Verbruggen Tim Heinemann Erik Manders Gesa von Bornstaedt Roel van Driel Thomas Höfer
author_sort	Paul Verbruggen
title	Robustness of DNA repair through collective rate control.
title_short	Robustness of DNA repair through collective rate control.
title_full	Robustness of DNA repair through collective rate control.
title_fullStr	Robustness of DNA repair through collective rate control.
title_full_unstemmed	Robustness of DNA repair through collective rate control.
title_sort	robustness of dna repair through collective rate control.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/76adebf17d254242a219f3d3304d1c38
work_keys_str_mv	AT paulverbruggen robustnessofdnarepairthroughcollectiveratecontrol AT timheinemann robustnessofdnarepairthroughcollectiveratecontrol AT erikmanders robustnessofdnarepairthroughcollectiveratecontrol AT gesavonbornstaedt robustnessofdnarepairthroughcollectiveratecontrol AT roelvandriel robustnessofdnarepairthroughcollectiveratecontrol AT thomashofer robustnessofdnarepairthroughcollectiveratecontrol
_version_	1718424673466712064

Robustness of DNA repair through collective rate control.

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