Genotype-Encoded UV Sensitivity in iPSC-Derived Human Melanocytes Reveals MX2 as a Physiological Amplifier of p53/p38-Mediated DNA Damage Signaling

Ultraviolet (UV) radiation induces DNA damage and oxidative stress in melanocytes, shaping pigmentation phenotypes and elevating photocarcinogenesis risk. Human models that capture donor-specific genetic determinants of UV sensitivity remain limited. Here, we establish a genotype-driven UV response model using induced pluripotent stem cell (iPSC)-derived melanocytes from donors carrying defined MC1R variants. Differentiated cells recapitulated melanocytic morphology, marker expression, and pigmentation consistent with donor sun-sensitivity traits. Following narrowband UVB exposure, UV-sensitive lines exhibited reduced survival, prolonged checkpoint activation, and delayed cyclobutane pyrimidine dimer (CPD) repair. Mechanistic analysis revealed that the interferon-regulated GTPase MX2 amplifies UV-induced p53 and p38 activation while promoting apoptosis independently of AKT. These findings identify MX2 as a physiological enhancer of DNA damage signaling in normal melanocytes, distinct from its interferon-mediated role in melanoma. Our study provides a human-relevant platform linking pigmentation genotype to UV resilience and supports iPSC-derived systems as New Approach Methodologies (NAMs) for mechanistic and translational phototoxicology.