NR4A nuclear receptors target Poly-ADP-Ribosylated DNA-PKcs protein to promote DNA repair

Journal article

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.

Authors: Munnur, D; Somers, J; Skalka, G; Weston, R; Jukes-Jones, R

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Cell Reports
• Volume: 26
• Issue: 8
• Pages: 2028-2036
• Publication date: 2019-02-19
• Acceptance date: 2019-01-23
• DOI: 10.1016/j.celrep.2019.01.083
• EISSN: 2211-1247
• ISSN: 2211-1247
• Pmid: 30784586
• Language: English
• Keywords: DNA-PK; transcription factors; non-homologous end joining; DNA repair; NR4A; poly-ADP-ribose; NHEJ; double-strand breaks; PARP; DSB