Abstract
Exposure of melanocytes to ultraviolet radiation (UVR) induces the formation of UV lesions that can produce deleterious effects in genomic DNA. Encounters of replication forks with unrepaired UV lesions can lead to several complex phenomena, such as the formation of DNA double-strand breaks (DSBs). The NR4A family of nuclear receptors are transcription factors that have been associated with mediating DNA repair functions downstream of the MC1R signaling pathway in melanocytes. In particular, emerging evidence shows that upon DNA damage, the NR4A2 receptor can translocate to sites of UV lesion by mechanisms requiring post-translational modifications within the N-terminal domain and at a serine residue in the DNA-binding domain at position 337. Following this, NR4A2 aids in DNA repair by facilitating chromatin relaxation, allowing accessibility for DNA repair machinery. Using A2058 and HT144 melanoma cells engineered to stably express wild-type or mutant forms of the NR4A2 proteins, we reveal that the expression of functional NR4A2 is associated with elevated cytoprotection against UVR. Conversely, knockdown of NR4A2 expression by siRNA results in a significant loss of cell viability after UV insult. By analyzing the kinetics of the ensuing 53BP1 and RAD51 foci following UV irradiation, we also reveal that the expression of mutant NR4A2 isoforms, lacking the ability to translocate, transactivate, or undergo phosphorylation, display compromised repair capacity.Implications: These data expand the understanding of the mechanism by which the NR4A2 nuclear receptor can facilitate DNA DSB repair. Mol Cancer Res; 15(9); 1184-96. ©2017 AACR.
Highlights
The NR4A proteins are a subgroup of the nuclear hormone receptor (NR) family of transcriptional regulators
We have previously identified the crucial role of Melanocortin-1-receptor activation (MC1R)-induced NR4A2 expression in melanocytic cells in response to ultraviolet radiation (UVR) DNA damage [11]
In light of these findings, it is tempting to speculate that NR4A2 protein functions as an early response factor upon DNA damage, with its role in promoting DNA repair implicated in studies using several different cell types [9, 10, 34]
Summary
The NR4A proteins are a subgroup of the nuclear hormone receptor (NR) family of transcriptional regulators. This subgroup of NRs is comprised of NR4A1 (Nur77), NR4A2 (Nurr1), and NR4A3 (Nor). Like classical NRs, NR4A receptors have an Nterminus domain (NTD), a highly conserved zinc-finger DNAbinding domain (DBD), and a carboxyl-terminal ligand-binding domain (LBD) [1]. It has been suggested that the NR4A receptors are true orphan receptors as no endogenous ligands have been identified to date. Crystal structure analysis suggests the NR4A receptors may be unable to accommodate binding of. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).
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