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Science 336 (6082): 728-732

Copyright © 2012 by the American Association for the Advancement of Science

Structural Basis for DNA Damage–Dependent Poly(ADP-ribosyl)ation by Human PARP-1

Marie-France Langelier, Jamie L. Planck, Swati Roy, John M. Pascal*

Abstract: Poly(ADP-ribose) polymerase–1 (PARP-1) (ADP, adenosine diphosphate) has a modular domain architecture that couples DNA damage detection to poly(ADP-ribosyl)ation activity through a poorly understood mechanism. Here, we report the crystal structure of a DNA double-strand break in complex with human PARP-1 domains essential for activation (Zn1, Zn3, WGR-CAT). PARP-1 engages DNA as a monomer, and the interaction with DNA damage organizes PARP-1 domains into a collapsed conformation that can explain the strong preference for automodification. The Zn1, Zn3, and WGR domains collectively bind to DNA, forming a network of interdomain contacts that links the DNA damage interface to the catalytic domain (CAT). The DNA damage–induced conformation of PARP-1 results in structural distortions that destabilize the CAT. Our results suggest that an increase in CAT protein dynamics underlies the DNA-dependent activation mechanism of PARP-1.

Department of Biochemistry and Molecular Biology, The Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

* To whom correspondence should be addressed. E-mail: john.pascal{at}kimmelcancercenter.org


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