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

## TL;DR

This study uses iPSC-derived melanocytes to show how genetic differences affect UV sensitivity and identifies MX2 as a key player in DNA damage signaling.

## Contribution

The study introduces a novel genotype-informed UV response model using iPSC-derived melanocytes and identifies MX2 as a physiological amplifier of DNA damage signaling.

## Key findings

- iPSC-derived melanocytes with specific MC1R variants recapitulate donor-linked UV sensitivity traits.
- MX2 amplifies UV-induced p53/p38 signaling and apoptosis independently of AKT.
- The model supports iPSC systems as new approach methodologies for phototoxicology.

## Abstract

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.