Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/45543
Title: NR4A Nuclear Receptors Target Poly-ADP-Ribosylated DNA-PKcs Protein to Promote DNA Repair.
Authors: Munnur, D
Somers, J
Skalka, G
Weston, R
Jukes-Jones, R
Bhogadia, M
Dominguez, C
Cain, K
Ahel, I
Malewicz, M
First Published: 19-Feb-2019
Publisher: Elsevier (Cell Press)
Citation: Cell Reports, 2019, 26 (8), pp. 2028-2036.e6
Abstract: Although poly-ADP-ribosylation (PARylation) of DNA repair factors had been well documented, its role in the repair of DNA double-strand breaks (DSBs) is poorly understood. NR4A nuclear orphan receptors were previously linked to DSB repair; however, their function in the process remains elusive. Classically, NR4As function as transcription factors using a specialized tandem zinc-finger DNA-binding domain (DBD) for target gene induction. Here, we show that NR4A DBD is bi-functional and can bind poly-ADP-ribose (PAR) through a pocket localized in the second zinc finger. Separation-of-function mutants demonstrate that NR4A PAR binding, while dispensable for transcriptional activity, facilitates repair of radiation-induced DNA double-strand breaks in G1. Moreover, we define DNA-PKcs protein as a prominent target of ionizing radiation-induced PARylation. Mechanistically, NR4As function by directly targeting poly-ADP-ribosylated DNA-PKcs to facilitate its autophosphorylation-promoting DNA-PK kinase assembly at DNA lesions. Selective targeting of the PAR-binding pocket of NR4A presents an opportunity for cancer therapy.
DOI Link: 10.1016/j.celrep.2019.01.083
eISSN: 2211-1247
Links: https://www.sciencedirect.com/science/article/pii/S2211124719301123?via%3Dihub
http://hdl.handle.net/2381/45543
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2019. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description: Supplemental Information includes four figures and one table and can be found with this article online at https://doi.org/10.1016/j.celrep.2019.01.083.
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

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