Kinetic gating mechanism of DNA damage recognition by Rad4/XPC

Xuejing Chen, Yogambigai Velmurugu, Guanqun Zheng, Beomseok Park, Yoonjung Shim, Youngchang Kim, Lili Liu, Bennett Van Houten, Chuan He, Anjum Ansari () and Jung-Hyun Min ()
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Xuejing Chen: University of Illinois at Chicago
Yogambigai Velmurugu: University of Illinois at Chicago
Guanqun Zheng: Institute for Biophysical Dynamics, The University of Chicago
Beomseok Park: University of Illinois at Chicago
Yoonjung Shim: University of Illinois at Chicago
Youngchang Kim: Structural Biology Center, Argonne National Laboratory
Lili Liu: University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, University of Pittsburgh
Bennett Van Houten: University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, University of Pittsburgh
Chuan He: Institute for Biophysical Dynamics, The University of Chicago
Anjum Ansari: University of Illinois at Chicago
Jung-Hyun Min: University of Illinois at Chicago

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract The xeroderma pigmentosum C (XPC) complex initiates nucleotide excision repair by recognizing DNA lesions before recruiting downstream factors. How XPC detects structurally diverse lesions embedded within normal DNA is unknown. Here we present a crystal structure that captures the yeast XPC orthologue (Rad4) on a single register of undamaged DNA. The structure shows that a disulphide-tethered Rad4 flips out normal nucleotides and adopts a conformation similar to that seen with damaged DNA. Contrary to many DNA repair enzymes that can directly reject non-target sites as structural misfits, our results suggest that Rad4/XPC uses a kinetic gating mechanism whereby lesion selectivity arises from the kinetic competition between DNA opening and the residence time of Rad4/XPC per site. This mechanism is further supported by measurements of Rad4-induced lesion-opening times using temperature-jump perturbation spectroscopy. Kinetic gating may be a general mechanism used by site-specific DNA-binding proteins to minimize time-consuming interrogations of non-target sites.

Date: 2015
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DOI: 10.1038/ncomms6849

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