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Title: Structural basis of detection and signaling of DNA single-strand breaks by human PARP-1

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:
 [1] ;  [2] ;  [3] ;  [4] ;  [4] ;  [3] ;  [3] ;  [4]
  1. Medical Research Council, Cambridge (United Kingdom); Ludwig-Maximilians-Univ. Munich, Munich (Germany)
  2. Medical Research Council, Cambridge (United Kingdom); The Univ. of Hong Kong, Hong Kong (China)
  3. Thomas Jefferson Univ., Philadelphia, PA (United States); Univ. de Montreal, Montreal, QC (Canada)
  4. Medical Research Council, Cambridge (United Kingdom)
Publication Date:
Grant/Contract Number:
AC02-05CH11231
Type:
Published Article
Journal Name:
Molecular Cell
Additional Journal Information:
Journal Volume: 60; Journal Issue: 5; Journal ID: ISSN 1097-2765
Publisher:
Elsevier - Cell Press
Research Org:
Thomas Jefferson Univ., Philadelphia, PA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1378282
Alternate Identifier(s):
OSTI ID: 1344495