NR4A nuclear receptors target poly-ADP-ribosylated DNA-PKcs protein to promote DNA repair

Munnur, D., Somers, J., Skalka, G., Weston, R., Jukes-Jones, R., Bhogadia, M., Dominguez, C., Cain, K., Ahel, I. and Malewicz, M. (2019) NR4A nuclear receptors target poly-ADP-ribosylated DNA-PKcs protein to promote DNA repair. Cell Reports, 26(8), 2028-2036.e6. (doi: 10.1016/j.celrep.2019.01.083) (PMID:30784586) (PMCID:PMC6381605)

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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.

Item Type:Articles
Additional Information:MRC (Medical Research Council, UK) funds M.M.’s work.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Somers, Miss Joanna and Skalka, Dr George
Authors: Munnur, D., Somers, J., Skalka, G., Weston, R., Jukes-Jones, R., Bhogadia, M., Dominguez, C., Cain, K., Ahel, I., and Malewicz, M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cell Reports
Publisher:Elsevier (Cell Press)
ISSN:2211-1247
ISSN (Online):2211-1247
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Cell Reports 26(8): 2028-2036.e6
Publisher Policy:Reproduced under a Creative Commons License

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