Solar ultraviolet B radiation (UVB) is one of the leading causes of various skin conditions, including photoaging, sunburn erythema, and melanoma. As a protective response, the skin has inbuilt defense mechanisms, including DNA repair, cell cycle, apoptosis, and melanin synthesis. Though DNA repair, cell cycle, and apoptosis are clock controlled, the circadian mechanisms associated with melanin synthesis are not well understood. Using human melanocytes and melanoma cells under synchronized clock conditions, we observed that the microphthalmia-associated transcription factor (MITF), a rate-limiting protein in melanin synthesis, is expressed rhythmically with 24-hr periodicity in the presence of circadian clock protein, BMAL1. Furthermore, we demonstrated that BMAL1 binds to the promoter region of MITF and transcriptionally regulates its expression, which positively influences melanin synthesis. Finally, we report that an increase in melanin levels due to BMAL1 overexpression protects human melanoma cells from UVB. In conclusion, our studies provide novel insights into the mechanistic role of the circadian clock in melanin synthesis and protection against UVB-mediated DNA damage and genomic instability.

中文翻译：

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昼夜节律时钟蛋白 BMAL1 通过 MITF 调节黑色素瘤细胞中的黑色素生成


太阳紫外线 B 辐射 (UVB) 是导致各种皮肤状况的主要原因之一，包括光老化、晒伤红斑和黑色素瘤。作为一种保护性反应，皮肤具有内置的防御机制，包括 DNA 修复、细胞周期、细胞凋亡和黑色素合成。尽管 DNA 修复、细胞周期和细胞凋亡受时钟控制，但与黑色素合成相关的昼夜节律机制尚不清楚。在同步时钟条件下使用人类黑色素细胞和黑色素瘤细胞，我们观察到小眼相关转录因子 (MITF)（黑色素合成的限速蛋白）在生物钟蛋白 BMAL1 存在的情况下以 24 小时周期性有节奏地表达。此外，我们证明 BMAL1 与MITF的启动子区域结合并转录调节其表达，从而对黑色素合成产生积极影响。最后，我们报告称，BMAL1 过度表达导致黑色素水平增加，可保护人类黑色素瘤细胞免受 UVB 的侵害。总之，我们的研究为生物钟在黑色素合成和防止 UVB 介导的 DNA 损伤和基因组不稳定性中的机制作用提供了新的见解。