| Title: |
NR4A Nuclear Receptors Target Poly-ADP-Ribosylated DNA-PKcs Protein to Promote DNA Repair |
| Authors: |
Deeksha Munnur, Joanna Somers, George Skalka, Ria Weston, Rebekah Jukes-Jones, Mohammed Bhogadia, Cyril Dominguez, Kelvin Cain, Ivan Ahel, Michal Malewicz |
| Source: |
Cell Reports, Vol 26, Iss 8, Pp 2028-2036.e6 (2019) |
| Publisher Information: |
Elsevier, 2019. |
| Publication Year: |
2019 |
| Collection: |
LCC:Biology (General) |
| Subject Terms: |
Biology (General), QH301-705.5 |
| More Details: |
Summary: 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. : DNA damage induces poly-ADP-ribosylation (PARylation) of repair factors recruited to DNA lesions. Munnur et al. identify a zinc-finger-type poly-ADP-ribose-binding domain in NR4A nuclear orphan receptors that targets PARylated DNA-PKcs repair kinase, facilitating its autophosphorylation and repair of double-strand DNA breaks. Keywords: DNA repair, double-strand breaks, DSB, NHEJ, NR4A, DNA-PK, poly-ADP-ribose, PARP, non-homologous end joining, transcription factors |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2211-1247 |
| Relation: |
http://www.sciencedirect.com/science/article/pii/S2211124719301123; https://doaj.org/toc/2211-1247 |
| DOI: |
10.1016/j.celrep.2019.01.083 |
| Access URL: |
https://doaj.org/article/fdedb83939404dee9e65c1e7a9fcb645 |
| Accession Number: |
edsdoj.fdedb83939404dee9e65c1e7a9fcb645 |
| Database: |
Directory of Open Access Journals |
