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Structural basis of R-loop recognition by the S9.6 monoclonal antibody

Author

Listed:
  • Charles Bou-Nader

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Ankur Bothra

    (National Institute of Allergy and Infectious Diseases)

  • David N. Garboczi

    (Research Technologies Branch, National Institute of Allergy and Infectious Diseases)

  • Stephen H. Leppla

    (National Institute of Allergy and Infectious Diseases)

  • Jinwei Zhang

    (National Institute of Diabetes and Digestive and Kidney Diseases)

Abstract

R-loops are ubiquitous, dynamic nucleic-acid structures that play fundamental roles in DNA replication and repair, chromatin and transcription regulation, as well as telomere maintenance. The DNA-RNA hybrid–specific S9.6 monoclonal antibody is widely used to map R-loops. Here, we report crystal structures of a S9.6 antigen-binding fragment (Fab) free and bound to a 13-bp hybrid duplex. We demonstrate that S9.6 exhibits robust selectivity in binding hybrids over double-stranded (ds) RNA and in categorically rejecting dsDNA. S9.6 asymmetrically recognizes a compact epitope of two consecutive RNA nucleotides via their 2′-hydroxyl groups and six consecutive DNA nucleotides via their backbone phosphate and deoxyribose groups. Recognition is mediated principally by aromatic and basic residues of the S9.6 heavy chain, which closely track the curvature of the hybrid minor groove. These findings reveal the molecular basis for S9.6 recognition of R-loops, detail its binding specificity, identify a new hybrid-recognition strategy, and provide a framework for S9.6 protein engineering.

Suggested Citation

  • Charles Bou-Nader & Ankur Bothra & David N. Garboczi & Stephen H. Leppla & Jinwei Zhang, 2022. "Structural basis of R-loop recognition by the S9.6 monoclonal antibody," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29187-7
    DOI: 10.1038/s41467-022-29187-7
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    References listed on IDEAS

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    1. Dmitry G. Vassylyev & Marina N. Vassylyeva & Jinwei Zhang & Murali Palangat & Irina Artsimovitch & Robert Landick, 2007. "Structural basis for substrate loading in bacterial RNA polymerase," Nature, Nature, vol. 448(7150), pages 163-168, July.
    2. Iris V. Hood & Jackson M. Gordon & Charles Bou-Nader & Frances E. Henderson & Soheila Bahmanjah & Jinwei Zhang, 2019. "Crystal structure of an adenovirus virus-associated RNA," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    3. Deepak Koirala & Yaming Shao & Yelena Koldobskaya & James R. Fuller & Andrew M. Watkins & Sandip A. Shelke & Evgeny V. Pilipenko & Rhiju Das & Phoebe A. Rice & Joseph A. Piccirilli, 2019. "A conserved RNA structural motif for organizing topology within picornaviral internal ribosome entry sites," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    4. Marianna Feretzaki & Michaela Pospisilova & Rita Valador Fernandes & Thomas Lunardi & Lumir Krejci & Joachim Lingner, 2020. "RAD51-dependent recruitment of TERRA lncRNA to telomeres through R-loops," Nature, Nature, vol. 587(7833), pages 303-308, November.
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    Cited by:

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    3. Abhishek Bharadwaj Sharma & Muhammad Khairul Ramlee & Joel Kosmin & Martin R. Higgs & Amy Wolstenholme & George E. Ronson & Dylan Jones & Daniel Ebner & Noor Shamkhi & David Sims & Paul W. G. Wijnhove, 2023. "C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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