The NR4A2 Nuclear Receptor Is Recruited to Novel Nuclear Foci in Response to UV Irradiation and Participates in Nucleotide Excision Repair

Jagirdar, Kasturee, Yin, Kelvin, Harrison, Matthew, Lim, Wen, Muscat, George E. O., Sturm, Richard A. and Smith, Aaron G. (2013) The NR4A2 Nuclear Receptor Is Recruited to Novel Nuclear Foci in Response to UV Irradiation and Participates in Nucleotide Excision Repair. PloS One, 8 11: e78075.1-e78075.13. doi:10.1371/journal.pone.0078075


Author Jagirdar, Kasturee
Yin, Kelvin
Harrison, Matthew
Lim, Wen
Muscat, George E. O.
Sturm, Richard A.
Smith, Aaron G.
Title The NR4A2 Nuclear Receptor Is Recruited to Novel Nuclear Foci in Response to UV Irradiation and Participates in Nucleotide Excision Repair
Journal name PloS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2013-11-01
Year available 2013
Sub-type Article (original research)
DOI 10.1371/journal.pone.0078075
Open Access Status DOI
Volume 8
Issue 11
Start page e78075.1
End page e78075.13
Total pages 14
Place of publication San Francisco, CA United States
Publisher Public Library of Science
Language eng
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.
Keyword Double Strand Breaks
Induced Dna Damage
Ubiquitin Ligase
Ionizing radiation
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 631510
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Biomedical Sciences Publications
Institute for Molecular Bioscience - Publications
 
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