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- W4308147072 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." @default.
- W4308147072 created "2022-11-08" @default.
- W4308147072 creator A5006304452 @default.
- W4308147072 creator A5019340034 @default.
- W4308147072 creator A5025385193 @default.
- W4308147072 creator A5039223835 @default.
- W4308147072 creator A5040154278 @default.
- W4308147072 creator A5040817018 @default.
- W4308147072 creator A5052481780 @default.
- W4308147072 creator A5085340246 @default.
- W4308147072 date "2022-11-02" @default.
- W4308147072 modified "2023-10-18" @default.
- W4308147072 title "Structural dynamics of DNA strand break sensing by PARP-1 at a single-molecule level" @default.
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