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

Published version
Peer-reviewed

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Authors

Somers, Joanna 
Jukes-Jones, Rebekah 

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.

Description

Keywords

DNA repair, DNA-PK, DSB, NHEJ, NR4A, PARP, double-strand breaks, non-homologous end joining, poly-ADP-ribose, transcription factors, Binding Sites, Cell Line, Tumor, DNA Repair, DNA-Activated Protein Kinase, HEK293 Cells, Humans, Nuclear Receptor Subfamily 4, Group A, Member 1, Poly ADP Ribosylation, Poly Adenosine Diphosphate Ribose, Protein Binding, Zinc Fingers

Journal Title

Cell Rep

Conference Name

Journal ISSN

2211-1247
2211-1247

Volume Title

26

Publisher

Elsevier BV