MITF Synchronizes UV-Protection Programs in the Skin

Sun exposure triggers an immediate stress response in the skin and a delayed pigmentation response that occurs hours afterward. Both of these responses serve to protect the skin from UV-induced mutations, but it is not clear how these skin protection programs are coordinated. Through investigation of the skin response to UVB radiation in mice, Malcov-Brog and colleagues found that the frequency of UV exposure controlled the balance between the two protection programs. UVB exposure every 48 hours increased the accumulation of pigment compared with radiation every 24 or 72 hours, and the 48-hour periodicity resulted in less DNA damage. The effect of UVB frequency was independent of the total amount of UVB exposure. The melanocyte master transcription factor MITF was responsible for synchronizing the stress response and pigmentation response, and it exhibited a damped oscillatory expression pattern for 48 hours following UVB exposure. Mathematical modelling of MITF dynamics revealed two layers of negative regulation that controlled the damped oscillatory behavior. MITF promoted expression of HIF1α to promote pigmentation, and HIF1α in turn inhibited MITF. Conversely, MITF derepressed miR-148a to favor proliferation and the stress response, and miR-148a also repressed MITF. These two negative feedback loops drove the damped oscillation of MITF, and provide a mechanism by which MITF may serve as a UV-protection timer. Consistent with his model, HIF1α inhibition reduced MITF oscillatory behavior whereas miR-148a depletion enhanced the oscillatory dynamics. Further, HIF1α inhibition prior to UV exposure reduced the enhanced skin pigmentation usually observed with exposure at a 48-hour interval. Collectively, these findings reveal a mechanism by which MITF synchronizes skin protection programs, suggest that exposure to UV every 48 hours may limit skin damage, and may provide insight into the role of MITF in melanoma.

Malcov-Brog H, Alpert A, Golan T, Parikh S, Nordlinger A, Netti F, et al. UV-protection timer controls linkage between stress and pigmentation skin protection systems. Mol Cell 2018;72:444–56.

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