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APE1 distinguishes DNA substrates in exonucleolytic cleavage by induced space-filling

Author

Listed:
  • Tung-Chang Liu

    (National Chiao Tung University
    National Chiao Tung University)

  • Chun-Ting Lin

    (National Chiao Tung University)

  • Kai-Cheng Chang

    (National Chiao Tung University)

  • Kai-Wei Guo

    (National Chiao Tung University)

  • Shuying Wang

    (National Cheng Kung University
    National Cheng Kung University
    National Cheng Kung University
    National Cheng Kung University)

  • Jhih-Wei Chu

    (National Chiao Tung University
    National Chiao Tung University
    National Chiao Tung University
    National Chiao Tung University)

  • Yu-Yuan Hsiao

    (National Chiao Tung University
    National Chiao Tung University
    National Chiao Tung University
    National Chiao Tung University)

Abstract

The exonuclease activity of Apurinic/apyrimidinic endonuclease 1 (APE1) is responsible for processing matched/mismatched terminus in various DNA repair pathways and for removing nucleoside analogs associated with drug resistance. To fill in the gap of structural basis for exonucleolytic cleavage, we determine the APE1-dsDNA complex structures displaying end-binding. As an exonuclease, APE1 does not show base preference but can distinguish dsDNAs with different structural features. Integration with assaying enzyme activity and binding affinity for a variety of substrates reveals for the first time that both endonucleolytic and exonucleolytic cleavage can be understood by an induced space-filling model. Binding dsDNA induces RM (Arg176 and Met269) bridge that defines a long and narrow product pocket for exquisite machinery of substrate selection. Our study paves the way to comprehend end-processing of dsDNA in the cell and the drug resistance relating to APE1.

Suggested Citation

  • Tung-Chang Liu & Chun-Ting Lin & Kai-Cheng Chang & Kai-Wei Guo & Shuying Wang & Jhih-Wei Chu & Yu-Yuan Hsiao, 2021. "APE1 distinguishes DNA substrates in exonucleolytic cleavage by induced space-filling," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20853-2
    DOI: 10.1038/s41467-020-20853-2
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    Cited by:

    1. Tyler M. Weaver & Nicole M. Hoitsma & Jonah J. Spencer & Lokesh Gakhar & Nicholas J. Schnicker & Bret D. Freudenthal, 2022. "Structural basis for APE1 processing DNA damage in the nucleosome," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Renye Yue & Zhe Li & Huiyi Liu & Youjuan Wang & Yuhang Li & Rui Yin & Baoli Yin & Haisheng Qian & Heemin Kang & Xiaobing Zhang & Guosheng Song, 2024. "Imaging-guided companion diagnostics in radiotherapy by monitoring APE1 activity with afterglow and MRI imaging," Nature Communications, Nature, vol. 15(1), pages 1-23, December.

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