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Stochastic and reversible assembly of a multiprotein DNA repair complex ensures accurate target site recognition and efficient repair

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Item Type:Article
Title:Stochastic and reversible assembly of a multiprotein DNA repair complex ensures accurate target site recognition and efficient repair
Creators Name:Luijsterburg, M.S., von Bornstaedt, G., Gourdin, A.M., Politi, A.Z., Mone, M.J., Warmerdam, D.O., Goedhart, J., Vermeulen, W., van Driel, R. and Hoefer, T.
Abstract:To understand how multiprotein complexes assemble and function on chromatin, we combined quantitative analysis of the mammalian nucleotide excision DNA repair (NER) machinery in living cells with computational modeling. We found that individual NER components exchange within tens of seconds between the bound state in repair complexes and the diffusive state in the nucleoplasm, whereas their net accumulation at repair sites evolves over several hours. Based on these in vivo data, we developed a predictive kinetic model for the assembly and function of repair complexes. DNA repair is orchestrated by the interplay of reversible protein-binding events and progressive enzymatic modifications of the chromatin substrate. We demonstrate that faithful recognition of DNA lesions is time consuming, whereas subsequently, repair complexes form rapidly through random and reversible assembly of NER proteins. Our kinetic analysis of the NER system reveals a fundamental conflict between specificity and efficiency of chromatin-associated protein machineries and shows how a trade off is negotiated through reversibility of protein binding.
Keywords:CHO Cells, Cultured Cells, DNA, DNA Damage, DNA Repair, DNA-Binding Proteins, Kinetics, Animals, Cricetinae, Cricetulus
Source:Journal of Cell Biology
ISSN:0021-9525
Publisher:Rockefeller University Press
Volume:189
Number:3
Page Range:445-463
Date:3 May 2010
Official Publication:https://doi.org/10.1083/jcb.200909175
PubMed:View item in PubMed

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