Structural dynamics of DNA strand break sensing by PARP-1 at a single-molecule level.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 11 2022
02 11 2022
Historique:
received:
10
02
2022
accepted:
14
10
2022
entrez:
3
11
2022
pubmed:
4
11
2022
medline:
5
11
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36323657
doi: 10.1038/s41467-022-34148-1
pii: 10.1038/s41467-022-34148-1
pmc: PMC9630430
doi:
Substances chimiques
Poly(ADP-ribose) Polymerase Inhibitors
0
X-ray Repair Cross Complementing Protein 1
0
DNA
9007-49-2
XRCC1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6569Subventions
Organisme : Medical Research Council
ID : MC_U105178934
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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