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

Abstract

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.

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

“…Nr4a1 overexpression in MIN6 cells and islets increased cell survival rates as measured by MTT, TUNEL assay and Caspase3 cleavage. Survivin protein binds to pro-caspase 3 and prevent Caspase 3 activation, reducing cell death [112]. Nr4a1 directly regulates Survivin expression through promoter binding.…”

The E2F1 transcription factor and RB tumor suppressor moonlight as DNA repair factors

“…Although recruitment of these transcription factors to sites of DNA damage is likely sequence-independent, the DNA-binding domains of many of these transcription factors are still required for their enrichment at sites of DNA damage [ 6 ]. Exceptions include E2F1, ATF2, NR4A, and SP1, which localize to sites of DNA damage independently of their DNA binding domains but may require phosphorylation by ATM, ATR or DNA-PK [ 7 – 13 ]. Loss-of-function experiments demonstrate that E2F1, ATF2, NR4A and SP1 each play important roles in DNA damage response signaling and/or in enhancing DNA repair efficiency, independent of transcription [ 7 , 8 , 12 , 14 ].…”

PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression

“…We focused on the link between the overexpression of fibroblast-secreted factors, including PLGF and BDNF, and the upregulation of NR4A1 transcription factor in TNBC epithelial cells, after inhibition of fibroblast PIK3Cδ. NR4A nuclear receptors are involved in metabolic, cardiovascular, and neurological functions, as well as in inflammation and cancer (62)(63)(64)(65). Despite the structural similarities of NR4A1, NR4A2, and NR4A3, they display distinctive roles and specific functions (66).…”