UV-protection timer controls a trade-off between skin protection systems. UV-protection timer controls a trade-off between skin protection systems

Tanning is a skin protection mechanism against UV radiation. Pigment production initiates hours after exposure, and the mechanism controlling this delay was unknown. Here we reveal a skin UV-protection timer, governed by damped oscillatory dynamics of the melanocyte master regulator, MITF, which after UV exposure, synchronizes regulatory programs, first cell survival and later pigmentation. Remarkably, the same amount of UV dosage resulted in higher pigmentation of human skin when given every-other day compared to daily exposure. Daily UV exposure appears to perturb MITF dynamics, thus re-ordering the survival and pigmentation programs. This demonstrates that the skin is more sensitive to frequency than quantity of UV exposure. Mathematical modeling identified a double negative regulatory loop involving HIF1a and microRNA-148a that regulates MITF dynamics. Our study suggests evolutionary leverage of the UV-protection timer, as it evolved to induce maximum protection with minimum damage for the reduction of skin cancer risk. Overall design: We analyzed 10 RNA samlpes from MNT-1 melanoma line upon treatment with cAMP (which mimic the sun exposure signaling) using Affymetrix Clarioum S Human Array platform. No techinical replicates were performed.