Document Type
Article
Publication Date
5-14-2019
Abstract
Poly(ADP-ribose) polymerase 1 (PARP-1) is a multidomain multifunctional nuclear enzyme involved in the regulation of the chromatin structure and transcription. PARP-1 consists of three functional domains: the N-terminal DNA-binding domain (DBD) containing three zinc fingers, the automodification domain (A), and the C-terminal domain, which includes the protein interacting WGR domain (W) and the catalytic (Cat) subdomain responsible for the poly(ADP ribosyl)ating reaction. The mechanisms coordinating the functions of these domains and determining the positioning of PARP-1 in chromatin remain unknown. Using multiple deletional isoforms of PARP-1, lacking one or another of its three domains, as well as consisting of only one of those domains, we demonstrate that different functions of PARP-1 are coordinated by interactions among these domains and their targets. Interaction between the DBD and damaged DNA leads to a short-term binding and activation of PARP-1. This "hit and run" activation of PARP-1 initiates the DNA repair pathway at a specific point. The long-term chromatin loosening required to sustain transcription takes place when the C-terminal domain of PARP-1 binds to chromatin by interacting with histone H4 in the nucleosome. This long-term activation of PARP-1 results in a continuous accumulation of pADPr, which maintains chromatin in the loosened state around a certain locus so that the transcription machinery has continuous access to DNA. Cooperation between the DBD and C-terminal domain occurs in response to heat shock (HS), allowing PARP-1 to scan chromatin for specific binding sites.
Recommended Citation
Thomas, MD, Colin; Ji, Yingbiao; Wu, Chao; Datz, Haily; Boyle, Cody; MacLeod, Brett; Patel, Shri; Ampofo, Michelle; Currie, Michelle; Harbin, Jonathan; Pechenkina, Kate; Lodhi, Niraj; Johnson, Sarah J.; and Tulin, Alexei V., "Hit and run versus long-term activation of PARP-1 by its different domains fine-tunes nuclear processes." (2019). Department of Medicine Faculty Papers. Paper 256.
https://jdc.jefferson.edu/medfp/256
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
31028139
Language
English
Comments
This article has been peer reviewed. It is the author’s final published version in Proceedings of the National Academy of Sciences of the United States of America, Volume 116, Issue 20, May 2019, Pages 9941-9946.
The published version is available at https://doi.org/10.1073/pnas.1901183116. Copyright © Thomas et al.