Abstract
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.
Highlights
Cockayne syndrome B protein (CSB), a member of the TC-nucleotide excision repair (NER) pathway, is essential for UV light-induced DNA damage repair
Restored CSB expression rescues UV hypersensitivity of testicular nuclear receptor 4 (TR4)-deficient cells. These results indicate that TR4 modulates UV sensitivity by promoting the TC-NER DNA repair pathway through transcriptional regulation of CSB
CSB Expression Is Dependent on TR4—To understand the molecular mechanisms by which TR4 modulates the NER pathway, we examined the expression of a battery of NER genes in TR4ϩ/ϩ and TR4Ϫ/Ϫ mouse tissues and cells
Summary
CSB, a member of the TC-NER pathway, is essential for UV light-induced DNA damage repair. 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 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. This study provides evidence for a molecular link between TR4, CSB expression, and UV light-induced cellular responses, which may lead to new information on the treatment of UV light-sensitive syndromes, skin cancer, and aging.
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