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

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.

Figure: Overview of the PARP-1/DNA crystal structure. (A) Modular domain architecture of human PARP-1. (B) Colorimetric assay of PARP-1 DNA-dependent automodification using the indicated domain combinations (see also Fig. S1 A,B). (C) Surface representation of the PARP-1/DNA structure. (D) A 90° rotation was applied to the view in C. (E) The Zn2 and BRCT domains (light grey) were manually positioned on the PARP-1/DNA structure using the structures of Zn2 and BRCT (PDB codes 3odc 2cok, respectively). The arrow accents the close proximity of AD and CAT.

Results from:
Langelier MF, Planck JL, Roy S, Pascal JM.
Science. 2012 May 11;336(6082):728-32. doi: 10.1126/science.1216338.
PMID: 22582261 [PubMed - indexed for MEDLINE]
PMCID: PMC3532513