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Structural dynamics of DNA strand break sensing by PARP-1 at a single-molecule level

Author

Listed:
  • Anna Sefer

    (Ulm University)

  • Eleni Kallis

    (Ulm University)

  • Tobias Eilert

    (Ulm University
    CoC CMC Statistics & Data Science)

  • Carlheinz Röcker

    (Ulm University)

  • Olga Kolesnikova

    (European Molecular Biology Laboratory (EMBL))

  • David Neuhaus

    (Cambridge Biomedical Campus)

  • Sebastian Eustermann

    (European Molecular Biology Laboratory (EMBL))

  • Jens Michaelis

    (Ulm University)

Abstract

Single-stranded breaks (SSBs) are the most frequent DNA lesions threatening genomic integrity. A highly kinked DNA structure in complex with human PARP-1 domains led to the proposal that SSB sensing in Eukaryotes relies on dynamics of both the broken DNA double helix and PARP-1’s multi-domain organization. Here, we directly probe this process at the single-molecule level. Quantitative smFRET and structural ensemble calculations reveal how PARP-1’s N-terminal zinc fingers convert DNA SSBs from a largely unperturbed conformation, via an intermediate state into the highly kinked DNA conformation. Our data suggest an induced fit mechanism via a multi-domain assembly cascade that drives SSB sensing and stimulates an interplay with the scaffold protein XRCC1 orchestrating subsequent DNA repair events. Interestingly, a clinically used PARP-1 inhibitor Niraparib shifts the equilibrium towards the unkinked DNA conformation, whereas the inhibitor EB47 stabilizes the kinked state.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34148-1
    DOI: 10.1038/s41467-022-34148-1
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    References listed on IDEAS

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    1. Syota Matsumoto & Simone Cavadini & Richard D. Bunker & Ralph S. Grand & Alessandro Potenza & Julius Rabl & Junpei Yamamoto & Andreas D. Schenk & Dirk Schübeler & Shigenori Iwai & Kaoru Sugasawa & Hit, 2019. "DNA damage detection in nucleosomes involves DNA register shifting," Nature, Nature, vol. 571(7763), pages 79-84, July.
    2. Marie-France Langelier & Levani Zandarashvili & Pedro M. Aguiar & Ben E. Black & John M. Pascal, 2018. "NAD+ analog reveals PARP-1 substrate-blocking mechanism and allosteric communication from catalytic center to DNA-binding domains," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    3. Syota Matsumoto & Simone Cavadini & Richard D. Bunker & Ralph S. Grand & Alessandro Potenza & Julius Rabl & Junpei Yamamoto & Andreas D. Schenk & Dirk Schübeler & Shigenori Iwai & Kaoru Sugasawa & Hit, 2019. "Publisher Correction: DNA damage detection in nucleosomes involves DNA register shifting," Nature, Nature, vol. 571(7764), pages 6-6, July.
    4. 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.
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