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Kinetic gating mechanism of DNA damage recognition by Rad4/XPC

Author

Listed:
  • 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
    Present address: Department of Biomedical Laboratory Science, Eulji University, Seongnam 461-713, Korea)

  • 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
    5117 Centre Avenue)

  • Bennett Van Houten

    (University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, University of Pittsburgh
    5117 Centre Avenue)

  • Chuan He

    (Institute for Biophysical Dynamics, The University of Chicago)

  • Anjum Ansari

    (University of Illinois at Chicago
    University of Illinois at Chicago)

  • Jung-Hyun Min

    (University of Illinois at Chicago)

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.

Suggested Citation

  • Xuejing Chen & Yogambigai Velmurugu & Guanqun Zheng & Beomseok Park & Yoonjung Shim & Youngchang Kim & Lili Liu & Bennett Van Houten & Chuan He & Anjum Ansari & Jung-Hyun Min, 2015. "Kinetic gating mechanism of DNA damage recognition by Rad4/XPC," Nature Communications, Nature, vol. 6(1), pages 1-10, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms6849
    DOI: 10.1038/ncomms6849
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    Cited by:

    1. Fangyuan Li & Heng Sun & Jiafeng Ren & Bo Zhang & Xi Hu & Chunyan Fang & Jiyoung Lee & Hongzhou Gu & Daishun Ling, 2022. "A nuclease-mimetic platinum nanozyme induces concurrent DNA platination and oxidative cleavage to overcome cancer drug resistance," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Marianna Genta & Giulia Ferrara & Riccardo Capelli & Diego Rondelli & Sarah Sertic & Martino Bolognesi & Menico Rizzi & Franca Rossi & David Jeruzalmi & Antonio Chaves-Sanjuan & Riccardo Miggiano, 2025. "Mechanistic understanding of UvrA damage detection and lesion hand-off to UvrB in Nucleotide Excision Repair," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    3. Anna Sefer & Eleni Kallis & Tobias Eilert & Carlheinz Röcker & Olga Kolesnikova & David Neuhaus & Sebastian Eustermann & Jens Michaelis, 2022. "Structural dynamics of DNA strand break sensing by PARP-1 at a single-molecule level," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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