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Cryo-EM structures of the XPF-ERCC1 endonuclease reveal how DNA-junction engagement disrupts an auto-inhibited conformation

Author

Listed:
  • Morgan Jones

    (Signalling and Structural Biology Laboratory, Francis Crick Institute)

  • Fabienne Beuron

    (Structural Electron Microscopy, The Institute of Cancer Research)

  • Aaron Borg

    (Mass Spectrometry Science Technology Platform, Francis Crick Institute)

  • Andrea Nans

    (Structural Biology of Cells and Viruses, Francis Crick Institute)

  • Christopher P. Earl

    (Signalling and Structural Biology Laboratory, Francis Crick Institute)

  • David C. Briggs

    (Signalling and Structural Biology Laboratory, Francis Crick Institute)

  • Ambrosius P. Snijders

    (Mass Spectrometry Science Technology Platform, Francis Crick Institute)

  • Maureen Bowles

    (Signalling and Structural Biology Laboratory, Francis Crick Institute)

  • Edward P. Morris

    (Structural Electron Microscopy, The Institute of Cancer Research)

  • Mark Linch

    (University College London Cancer Institute)

  • Neil Q. McDonald

    (Signalling and Structural Biology Laboratory, Francis Crick Institute
    Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College)

Abstract

The structure-specific endonuclease XPF-ERCC1 participates in multiple DNA damage repair pathways including nucleotide excision repair (NER) and inter-strand crosslink repair (ICLR). How XPF-ERCC1 is catalytically activated by DNA junction substrates is not currently understood. Here we report cryo-electron microscopy structures of both DNA-free and DNA-bound human XPF-ERCC1. DNA-free XPF-ERCC1 adopts an auto-inhibited conformation in which the XPF helical domain masks the ERCC1 (HhH)2 domain and restricts access to the XPF catalytic site. DNA junction engagement releases the ERCC1 (HhH)2 domain to couple with the XPF-ERCC1 nuclease/nuclease-like domains. Structure-function data indicate xeroderma pigmentosum patient mutations frequently compromise the structural integrity of XPF-ERCC1. Fanconi anaemia patient mutations in XPF often display substantial in-vitro activity but are resistant to activation by ICLR recruitment factor SLX4. Our data provide insights into XPF-ERCC1 architecture and catalytic activation.

Suggested Citation

  • Morgan Jones & Fabienne Beuron & Aaron Borg & Andrea Nans & Christopher P. Earl & David C. Briggs & Ambrosius P. Snijders & Maureen Bowles & Edward P. Morris & Mark Linch & Neil Q. McDonald, 2020. "Cryo-EM structures of the XPF-ERCC1 endonuclease reveal how DNA-junction engagement disrupts an auto-inhibited conformation," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14856-2
    DOI: 10.1038/s41467-020-14856-2
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    Cited by:

    1. Jina Yu & Chunli Yan & Tanmoy Paul & Lucas Brewer & Susan E. Tsutakawa & Chi-Lin Tsai & Samir M. Hamdan & John A. Tainer & Ivaylo Ivanov, 2024. "Molecular architecture and functional dynamics of the pre-incision complex in nucleotide excision repair," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Xintao Song & Lei Bao & Chenjie Feng & Qiang Huang & Fa Zhang & Xin Gao & Renmin Han, 2024. "Accurate Prediction of Protein Structural Flexibility by Deep Learning Integrating Intricate Atomic Structures and Cryo-EM Density Information," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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