The NR4A2 nuclear receptor is recruited to novel nuclear foci in response to UV irradiation and participates in nucleotide excision repair.
Ultraviolet radiation (UVR) is one of the most common mutagens encountered by humans and induces the formation of cyclobutane pyrimidine dimers (CPDs) and pyrimidine-(6-4)-pyrimidone photoproduct (6-4PP) lesions in the genomic DNA. To prevent the accumulation of deleterious mutations these lesions must be efficiently repaired, primarily by nucleotide excision repair. We have previously demonstrated that the NR4A family of nuclear receptors are crucial mediators of the DNA repair function of the MC1R signalling pathway in melanocytes. Here we explore the role of the NR4A2 protein in the DNA repair process further. Using EYFP tagged-NR4A2 we have demonstrated a UVR induced recruitment to distinct nuclear foci where they co-localise with known DNA repair proteins. We reveal that the N-terminal domain of the receptor is required for this translocation and identify a role for p38 and PARP signalling in this process. Moreover disruption of the functional integrity of the Ligand Binding Domain of the receptor by deleting the terminal helix 12 effectively blocks co-localisation of the receptor with DNA repair factors. Restored co-localisation of the mutant receptor with DNA repair proteins in the presence of a Histone Deacetylase Inhibitor suggests that impaired chromatin accessibility underpins the mis-localisation observed. Finally NR4A2 over-expression facilitated a more efficient clearance of UVR induced CPD and 6-4PP lesions. Taken together these data uncover a novel role for the NR4A nuclear receptors as direct facilitators of nucleotide excision repair.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
Kasturee
K
Jagirdar
Kelvin
K
Yin
Matthew
M
Harrison
Wen
W
Lim
George E O
GE
Muscat
Richard A
RA
Sturm
Aaron G
AG
Smith
D001665:Binding Sites; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism* / Q000528:radiation effects; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D014466:Ultraviolet Rays
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; C012589:trichostatin A; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D045643:DNA Repair Enzymes