Structural Basis of Detection and Signaling of DNA Single-Strand Breaks by Human PARP-1
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. Automodifcation in cis explains the subsequent release of monomeric PARP-1 from DNA, allowing repair and replication to proceed. Finally, our results provide a molecular framework for understanding PARP inhibitor action and, more generally, allosteric control of dynamic, multi-domain proteins.
- Authors:
- Publication Date:
- Research Org.:
- Thomas Jefferson Univ., Philadelphia, PA (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1378282
- Alternate Identifier(s):
- OSTI ID: 1344495
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Published Article
- Journal Name:
- Molecular Cell
- Additional Journal Information:
- Journal Name: Molecular Cell Journal Volume: 60 Journal Issue: 5; Journal ID: ISSN 1097-2765
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Eustermann, Sebastian, Wu, Wing-Fung, Langelier, Marie-France, Yang, Ji-Chun, Easton, Laura E., Riccio, Amanda A., Pascal, John M., and Neuhaus, David. Structural Basis of Detection and Signaling of DNA Single-Strand Breaks by Human PARP-1. United States: N. p., 2015.
Web. doi:10.1016/j.molcel.2015.10.032.
Eustermann, Sebastian, Wu, Wing-Fung, Langelier, Marie-France, Yang, Ji-Chun, Easton, Laura E., Riccio, Amanda A., Pascal, John M., & Neuhaus, David. Structural Basis of Detection and Signaling of DNA Single-Strand Breaks by Human PARP-1. United States. https://doi.org/10.1016/j.molcel.2015.10.032
Eustermann, Sebastian, Wu, Wing-Fung, Langelier, Marie-France, Yang, Ji-Chun, Easton, Laura E., Riccio, Amanda A., Pascal, John M., and Neuhaus, David. Tue .
"Structural Basis of Detection and Signaling of DNA Single-Strand Breaks by Human PARP-1". United States. https://doi.org/10.1016/j.molcel.2015.10.032.
@article{osti_1378282,
title = {Structural Basis of Detection and Signaling of DNA Single-Strand Breaks by Human PARP-1},
author = {Eustermann, Sebastian and Wu, Wing-Fung and Langelier, Marie-France and Yang, Ji-Chun and Easton, Laura E. and Riccio, Amanda A. and Pascal, John M. and Neuhaus, David},
abstractNote = {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. Automodifcation in cis explains the subsequent release of monomeric PARP-1 from DNA, allowing repair and replication to proceed. Finally, our results provide a molecular framework for understanding PARP inhibitor action and, more generally, allosteric control of dynamic, multi-domain proteins.},
doi = {10.1016/j.molcel.2015.10.032},
journal = {Molecular Cell},
number = 5,
volume = 60,
place = {United States},
year = {Tue Dec 01 00:00:00 EST 2015},
month = {Tue Dec 01 00:00:00 EST 2015}
}
https://doi.org/10.1016/j.molcel.2015.10.032
Web of Science
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