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

Cell Rep. 2019 Feb 19;26(8):2028-2036.e6. doi: 10.1016/j.celrep.2019.01.083.

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.

Keywords: DNA repair; DNA-PK; DSB; NHEJ; NR4A; PARP; double-strand breaks; non-homologous end joining; poly-ADP-ribose; transcription factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line, Tumor
  • DNA Repair*
  • DNA-Activated Protein Kinase / chemistry
  • DNA-Activated Protein Kinase / metabolism*
  • HEK293 Cells
  • Humans
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / chemistry
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Poly ADP Ribosylation
  • Poly Adenosine Diphosphate Ribose / chemistry
  • Poly Adenosine Diphosphate Ribose / metabolism
  • Protein Binding
  • Zinc Fingers

Substances

  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Poly Adenosine Diphosphate Ribose
  • DNA-Activated Protein Kinase
  • PRKDC protein, human