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

Anna Sefer, Eleni Kallis, Tobias Eilert, Carlheinz Röcker, Olga Kolesnikova, David Neuhaus, Sebastian Eustermann () and Jens Michaelis ()
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Anna Sefer: Ulm University
Eleni Kallis: Ulm University
Tobias Eilert: Ulm University
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

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34148-1

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