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Mol Cell. 2015 Dec 3;60(5):742-754. doi: 10.1016/j.molcel.2015.10.032. Epub 2015 Nov 25.

Structural Basis of Detection and Signaling of DNA Single-Strand Breaks by Human PARP-1.

Author information

1
Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
2
Department of Molecular Biology and Biochemistry, Sidney Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Bluemle Life Sciences Building, Room 804, Philadelphia, PA 19107, USA.
3
Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address: dn@mrc-lmb.cam.ac.uk.

Abstract

Poly(ADP-ribose)polymerase 1 (PARP-1) is a key eukaryotic stress sensor that responds in seconds to DNA single-strand breaks (SSBs), the most frequent genomic damage. A burst of poly(ADP-ribose) synthesis initiates DNA damage response, whereas PARP-1 inhibition kills BRCA-deficient tumor cells selectively, providing the first anti-cancer therapy based on synthetic lethality. However, the mechanism underlying PARP-1's function remained obscure; inherent dynamics of SSBs and PARP-1's multi-domain architecture hindered structural studies. Here we reveal the structural basis of SSB detection and how multi-domain folding underlies the allosteric switch that determines PARP-1's signaling response. Two flexibly linked N-terminal zinc fingers recognize the extreme deformability of SSBs and drive co-operative, stepwise self-assembly of remaining PARP-1 domains to control the activity of the C-terminal catalytic domain. Automodification in cis explains the subsequent release of monomeric PARP-1 from DNA, allowing repair and replication to proceed. Our results provide a molecular framework for understanding PARP inhibitor action and, more generally, allosteric control of dynamic, multi-domain proteins.

PMID:
26626479
PMCID:
PMC4678113
DOI:
10.1016/j.molcel.2015.10.032
[Indexed for MEDLINE]
Free PMC Article

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