Abstract
SummaryAlthough 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.
Highlights
Nuclear DNA is under a constant threat of damage by reactive oxygen species, aberrant activity of enzymes and/or exogenous radiation
Conserved Zn2 of NR4A2 Encodes a PAR-Binding Domain Given that NR4A recruitment to DNA damage sites depends on PAR (Figure 1A) (Jagirdar et al, 2013; Malewicz et al, 2011), we asked whether NR4As could bind PAR directly
The ability to bind PAR resides in the second zinc finger (Zn2) of the NR4A2 DNA-binding domain (DBD) (Figures 1B and 1C)
Summary
Nuclear DNA is under a constant threat of damage by reactive oxygen species, aberrant activity of enzymes and/or exogenous radiation. Efficient DNA repair is essential for survival of all organisms (Jackson and Bartek, 2009). Doublestrand breaks (DSBs) can be repaired by several pathways, classical non-homologous end joining (c-NHEJ) is responsible for the bulk of DSB repair (Waters et al, 2014). NHEJ is initiated by sequence-independent binding of Ku70/Ku80 dimers to exposed DNA ends at DSBs. DNA-bound Ku rapidly recruits DNA-PKcs kinase, resulting in its activation and DNA-PKcs auto
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call