Testicular Nuclear Receptor 4 (TR4) Regulates UV Light-induced Responses via Cockayne Syndrome B Protein-mediated Transcription-coupled DNA Repair

George Whipple Lab for Cancer Research, Departments of Pathology and Urology, University of Rochester Medical Center, Rochester, New York 14642, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 09/2011; 286(44):38103-8. DOI: 10.1074/jbc.M111.259523
Source: PubMed


UV irradiation is one of the major external insults to cells and can cause skin aging and cancer. In response to UV light-induced DNA damage, the nucleotide excision repair (NER) pathways are activated to remove DNA lesions. We report here that testicular nuclear receptor 4 (TR4), a member of the nuclear receptor family, modulates DNA repair specifically through the transcription-coupled (TC) NER pathway but not the global genomic NER pathway. The level of Cockayne syndrome B protein (CSB), a member of the TC-NER pathway, is 10-fold reduced in TR4-deficient mouse tissues, and TR4 directly regulates CSB at the transcriptional level. Moreover, restored CSB expression rescues UV hypersensitivity of TR4-deficient cells. Together, these results indicate that TR4 modulates UV sensitivity by promoting the TC-NER DNA repair pathway through transcriptional regulation of CSB. These results may lead to the development of new treatments for UV light-sensitive syndromes, skin cancer, and aging.

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    • "DNA damage is thought to be the common pathway causing aging. Liu et al. (2011b) reported that TR4 modulates ultraviolet (UV) sensitivity by promoting the transcription-coupled NER (TC-NER) DNA repair pathway through transcriptional regulation of CSB. Yan et al. (2012) found that deficiency of TR4 abrogates growth arrest and DNA-damage-inducible protein GADD45 alpha (Gadd45α) expression, and increases cytotoxicity induced by ionizing radiation. "
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    ABSTRACT: Testicular nuclear receptor 4 (TR4), also known as NR2C2 (nuclear receptor subfamily 2, group C, member 2), is a transcriptional factor and a member of the nuclear receptor family. TR4 was initially cloned from human and rat hypothalamus, prostate, and testes libraries. For almost two decades, its specific tissue distribution, genomic organization, and chromosomal assignment have been well investigated in humans and animals. However, it has been very difficult to study TR4's physiological functions due to a lack of specific ligands. Gene knock-out animal techniques provide an alternative approach for defining the biological functions of TR4. In vivo studies of TR4 gene knockout mice (TR4) found that they display severe spinal curvature, subfertility, premature aging, and prostate prostatic intraepithelial neoplasia (PIN) development. Upstream modulators, downstream target gene regulation, feedback mechanisms, and differential modulation mediated by the recruitment of other nuclear receptors and coregulators have been identified in studies using the TR4 phenotype. With the establishment of a tissue-specific TR4 mouse model, research on TR4 will be more convenient in the future.
    Journal of Zhejiang University SCIENCE B 03/2013; 14(3):171-7. DOI:10.1631/jzus.B1200357 · 1.28 Impact Factor
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    ABSTRACT: The testicular receptor 4 (TR4) is a member of the nuclear receptor superfamily that controls various biological activities. A protective role of TR4 against oxidative stress has recently been discovered. We here examined the protective role of TR4 against ionizing radiation (IR) and found that small hairpin RNA mediated TR4 knockdown cells were highly sensitive to IR-induced cell death. IR exposure increased the expression of TR4 in scramble control small hairpin RNA expressing cells but not in TR4 knockdown cells. Examination of IR-responsive molecules found that the expression of Gadd45a, the growth arrest and DNA damage response gene, was dramatically decreased in Tr4 deficient (TR4KO) mice tissues and could not respond to IR stimulation in TR4KO mouse embryonic fibroblast cells. This TR4 regulation of GADD45A was at the transcriptional level. Promoter analysis identified four potential TR4 response elements located in intron 3 and exon 4 of the GADD45A gene. Reporter and chromatin immunoprecipitation (ChIP) assays provided evidence indicating that TR4 regulated the GADD45A expression through TR4 response elements located in intron 3 of the GADD45A gene. Together, we find that TR4 is essential in protecting cells from IR stress. Upon IR challenges, TR4 expression is increased, thereafter inducing GADD45A through transcriptional regulation. As GADD45A is directly involved in the DNA repair pathway, this suggests that TR4 senses genotoxic stress and up-regulates GADD45A expression to protect cells from IR-induced genotoxicity.
    Cellular & Molecular Biology Letters 03/2012; 17(2):309-22. DOI:10.2478/s11658-012-0012-9 · 1.59 Impact Factor
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    ABSTRACT: Prostate cancer (PCa) stem/progenitor cells are known to have higher chemo-resistance than non-stem/progenitor cells, but the underlying molecular mechanism remains unclear. We found the expression of testicular nuclear receptor 4 (TR4) is significantly higher in PCa CD133+ stem/progenitor cells compared to CD133- non-stem/progenitor cells. Knocking down of TR4 levels in the established PCa stem/progenitor cells (PCSCs) and the CD133+ population of the C4-2 PCa cell line with lentiviral TR4-siRNA led to increased drug sensitivity to the two commonly used chemotherapeutic drugs, docetaxel and etoposide, judging from significantly reduced IC50 values and increased apoptosis in the TR4 knocked down cells. Mechanism dissection studies found that suppression of TR4 in these stem/progenitor cells led to down-regulation of Oct4 expression, which in turn, down-regulated the IL-1 receptor antagonist (IL1Ra) expression. Neutralization experiments via adding these molecules into the TR4 knocked-down PCa stem/progenitor cells reversed the chemo-resistance, suggesting that the TR4-Oct4-IL1Ra axis may play a critical role in the development of chemo-resistance in the PCa stem/progenitor cells. Together, these studies suggest that targeting TR4 may alter chemo-resistance of PCa stem/progenitor cells and this finding provides the possibility of targeting TR4 as a new and better approach to overcome the chemo-resistance problem in PCa therapeutics.
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