NAD+ analog reveals PARP-1 substrate-blocking mechanism and allosteric communication from catalytic center to DNA-binding domains

Nature Communications
Marie-France LangelierJohn M Pascal

Abstract

PARP-1 cleaves NAD+ and transfers the resulting ADP-ribose moiety onto target proteins and onto subsequent polymers of ADP-ribose. An allosteric network connects PARP-1 multi-domain detection of DNA damage to catalytic domain structural changes that relieve catalytic autoinhibition; however, the mechanism of autoinhibition is undefined. Here, we show using the non-hydrolyzable NAD+ analog benzamide adenine dinucleotide (BAD) that PARP-1 autoinhibition results from a selective block on NAD+ binding. Following DNA damage detection, BAD binding to the catalytic domain leads to changes in PARP-1 dynamics at distant DNA-binding surfaces, resulting in increased affinity for DNA damage, and providing direct evidence of reverse allostery. Our findings reveal a two-step mechanism to activate and to then stabilize PARP-1 on a DNA break, indicate that PARP-1 allostery influences persistence on DNA damage, and have important implications for PARP inhibitors that engage the NAD+ binding site.

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Methods Mentioned

BETA
NMR
isothermal titration calorimetry
gel filtration

Software Mentioned

PHASER
SCALA
KaleidaGraph
XDS
Origin
HXMS
PYMOL Molecular Graphics System
MATLAB
Phenix suite
COOT

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