Mathematical modeling of nucleotide excision repair reveals efficiency of sequential assembly strategies.
Nucleotide excision repair (NER) requires the concerted action of many different proteins that assemble at sites of damaged DNA in a sequential fashion. We have constructed a mathematical model delineating hallmarks and general characteristics for NER. We measured the assembly kinetics of the putative damage-recognition factor XPC-HR23B at sites of DNA damage in the nuclei of living cells. These and other in vivo kinetic data allowed us to scrutinize the dynamic behavior of the nucleotide excision repair process in detail. A sequential assembly mechanism appears remarkably advantageous in terms of repair efficiency. Alternative mechanisms for repairosome formation, including random assembly and preassembly, can readily become kinetically unfavorable. Based on the model, new experiments can be defined to gain further insight into this complex process and to critically test model predictions. Our work provides a kinetic framework for NER and rationalizes why many multiprotein processes within the cell nucleus show sequential assembly strategy.
Politi
Antonio
A
Department of Theoretical Biophysics, Institute of Biology, Humboldt University, Invalidenstrasse 42, 10115 Berlin, Germany.
Moné
Martijn J
MJ
Houtsmuller
Adriaan B
AB
Hoogstraten
Deborah
D
Vermeulen
Wim
W
Heinrich
Reinhart
R
van Driel
Roel
R
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D017930:Genes, Reporter; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D011485:Protein Binding; D051758:Transcription Factor TFIIH; D019473:Transcription Factors, TFII / Q000502:physiology
D004268:DNA-Binding Proteins; D019473:Transcription Factors, TFII; D051758:Transcription Factor TFIIH; C086984:XPC protein, human