NR4A Nuclear Receptors Target Poly-ADP-Ribosylated DNA-PKcs Protein to Promote DNA Repair

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 factor