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- Title
NAD<sup>+</sup> analog reveals PARP-1 substrate-blocking mechanism and allosteric communication from catalytic center to DNA-binding domains.
- Authors
Langelier, Marie-France; Zandarashvili, Levani; Aguiar, Pedro M.; Black, Ben E.; Pascal, John M.
- 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 multidomain 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.
- Subjects
ALLOSTERIC regulation; DEOXYRIBOZYMES; DNA damage; CATALYTIC domains; CD38 antigen; NAD (Coenzyme); BINDING sites
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-03234-8