Structural basis for DNA-dependent poly(ADP-ribosyl)ation by human PARP-1

By M. Langelier, J. Planck, Swati Roy, J. Pascal. Science, 2012

642 citations recorded by the source corpus.

Dissecting DNA Repair Covalent modification of proteins can be a crucial regulatory event. Poly(ADP-ribose) polymerase 1 (PARP-1) (ADP, adenosine diphosphate) synthesizes poly(ADP-ribose), which is attached to and regulates proteins involved in DNA repair. Langelier et al. (p. 728; see the Perspective by Gagné et al.) use x-ray crystallography and biochemical analysis to demonstrate how PARP-1 detects DNA damage and how the interaction with DNA is coupled to poly(ADP-ribosyl)ation activity. An enzyme that binds to damaged DNA undergoes a structural reorganization that enhances its catalytic activity. 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.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/5b42148347469928c49e3b7ead55d6eeea72fd43

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Citations in the corpus

Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib (2013, background): “The binding of PARP inhibitor to the catalytic pocket of PARP1 and PARP2may enhance thebindingbetweenDNAand theDNA-bindingdomains of PARP, which would be the converse allosteric effect produced by the binding of PARP toDNA,which induces conformational distortions that stimulate the catalytic domain ”
PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes (2017, background): “Moreover, while PARP-2 and PARP-3 share the allosteric activation mechanismwith PARP-1, they require 5′ phosphorylation at the DNA breaks for activation, unlike PARP-1 (Langelier et al. 2014).”