| Title |
Genotype-encoded UV sensitivity in iPSC-derived human melanocytes reveals MX2 as a physiological amplifier of p53/p38-mediated DNA damage signaling |
| Authors |
Ramirez-Salazar, Eric ; Slipicevic, Ana ; Juralevičiūtė, Marina ; Li, Ling ; Harland, Mark ; O’Shea, Sally ; Field, Sinead ; Newton-Bishop, Julia ; Herlyn, Meenhard |
| DOI |
10.3390/ijms27062617 |
| Full Text |
|
| Is Part of |
International journal of molecular sciences.. Basel : MDPI AG. 2026, vol. 27, iss. 6, art. no. 2617, p. [1-21].. eISSN 1422-0067 |
| Keywords [eng] |
induced pluripotent stem cells ; iPSC-derived melanocytes ; ultraviolet radiation ; MC1R variants ; DNA damage response ; MX2 ; p53 signaling ; new approach methodologies |
| Abstract [eng] |
Ultraviolet (UV) radiation induces DNA damage and oxidative stress in melanocytes, shaping pigmentation phenotypes and elevating photocarcinogenesis risk. Human models that capture donor-linked genetic determinants of UV sensitivity remain limited. Here, we establish a genotype-informed 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, melanocyte lines with higher UV sensitivity showed reduced survival, prolonged checkpoint activation, and CPD-associated DNA damage signaling dynamics. Mechanistic analysis suggests that the interferon-regulated GTPase MX2 is associated with amplification of UV-induced p53 and p38 activation while promoting apoptosis independently of AKT. These findings support 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. |
| Published |
Basel : MDPI AG |
| Type |
Journal article |
| Language |
English |
| Publication date |
2026 |
| CC license |
|
