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Circadian Clock Protein BMAL1 Protect Against UVB Damage

The skin is the largest organ of the human body composed of the epidermis (upper or outer layer) and the dermis (lower or inner layer). The epidermis, which is made up of three kinds of cells: keratinocytes, basal cells, and melanocytes, is susceptible to DNA damage caused by exposure to harmful solar ultraviolet radiation (UVR). In fact, solar ultraviolet B radiation (UVB) is one of the leading causes of various skin conditions, including photoaging, sunburn erythema, and skin cancers like melanoma. As a protective response, the skin has defense mechanisms, including DNA repair and melanin synthesis.

Melanin is a dark pigment produced by melanocytes through a process called melanogenesis responsible for skin color. It is known to be a potent UBV absorber, which protects keratinocytes in the epidermis from UVB-induced damage. Additionally, the body’s circadian clock, responsible for maintaining physiological and behavioral rhythms, plays a role in skin cell homeostasis and initiating mechanisms to protect from environmental stressors, including UVR. Dysregulation of these cellular processes due to clock disruption caused by shift work, and abnormal eating, is linked to increased prevalence of various skin pathologies like melanoma.

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The circadian clock and melanin synthesis each play a vital role in protection against solar UVB-induced DNA damage. The mammalian circadian clock is controlled by a transcription-translation feedback loop consisting of transcriptional activators CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein-1), and repressors CRY1/CRY2 and PER1/PER2. Previous research indicated that circadian clock genes BMAL1 and PER1 influenced melanogenesis by exerting effects on microphthalmia-associated transcription factor (MITF), a rate-limiting protein in melanin synthesis, but the mechanistic link has yet to be established.

Sarkar and Colleagues performed studies with both normal and melanoma cells in both mouse and human systems in vitro to examine gene expression levels of BMAL1, MITF, and PER2 using RT-PCR. Synchronized human melanocytes and melanoma cells were cultured in Lifeline’s DermaLife Ma Melanocyte Complete Medium for these experiments. Initial experiments to determine which clock genes were linked to melanogenesis showed that melanin levels in the absence of PER2 (PER2 KO), a negative regulator of BMAL1, were elevated compared with wild-type cells leading the authors to postulate that BMAL1 is responsible for increased MITF levels.

BMAL1-targeted chromatin immunoprecipitation (ChIP) assay in mice demonstrated that BMAL1 binds to the MITF promoter region and transcriptionally regulates its expression, which positively influences melanin synthesis. This was confirmed when BMAL1 overexpression in human melanoma cells led to increased mRNA and protein levels of MITF.  MITF expression was found to be directly and rhythmically controlled by BMAL1 through time-course gene expression analysis through a circadian cycle. In cells where BMAL1 was knocked down by siRNA, circadian rhythmicity of MITF expression was lost, compared to wildtype cells.

To determine the physiological effect of BMAL1-regulated melanin synthesis in UVB exposed cells, the researchers measured the survival of cells post-UVB exposure normalized to non-UVB-treated conditions. The survival data suggest that increased melanogenesis in cells overexpressing BMAL1 enhances protection against UVB irradiation.

Together, the study identifies a new mechanistic link between the circadian clock and melanin synthesis in the skin where the core clock protein BMAL1 transcriptionally regulates MITF expression based on circadian rhythms. The positive effect of the BMAL1-MITF axis on melanogenesis could serve as a potential therapeutic target to enhance melanin synthesis, increasing protection against UVB-induced genomic instability, in future sunscreen development strategies.

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