Abstract
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.
Highlights
The NR4A transcriptional regulators are a 3 member orphan sub-family of Nuclear Hormone Receptors that includes NR4A1 (Nur77/NGFI-B), NR4A2 (Nurr1, NOT) and NR4A3 (NOR-1, MINOR)
In light of our previous demonstration that the NR4A proteins were pivotal to Melanocortin-1 Receptor (MC1R) mediated DNA repair in melanocytes [3], we wished to determine if a similar NR4A1 recruitment to nuclear foci would occur in response to UV radiation and if this phenomenon would occur for the NR4A2 protein
Co-localisation of proteins involved in the recognition and repair of DNA damage such as cH2A.X, and nucleotide excision repair proteins, XPC and DDB2, at these foci suggest these are sites of active DNA damage repair
Summary
The NR4A transcriptional regulators are a 3 member orphan sub-family of Nuclear Hormone Receptors that includes NR4A1 (Nur77/NGFI-B), NR4A2 (Nurr, NOT) and NR4A3 (NOR-1, MINOR). NR4A proteins contain the highly conserved zinc-finger DNA binding domain (DBD) and carboxy-terminal ligand binding domain (LBD) characteristic of nuclear receptors [1,2]. While no endogenous ligands have been identified for these receptors, and the crystal structure of the LBD suggests they are true orphan receptors, NR4A proteins have been found to be tightly regulated by numerous signalling pathways at both the transcriptional and post-translational level allowing these proteins to function rapidly and to co-ordinate diverse cellular responses. MC1R is a G-protein coupled receptor that is a central regulator of pigmentation in melanocytes and has been shown to facilitate DNA repair and cytoprotection following exposure to ultraviolet UV radiation (UVR). Our studies demonstrated that the NR4A1 and NR4A2 proteins are required for the ability of MC1R to enhance DNA repair following UVR [3]
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