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Adelson Medical Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100005984","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C588\/A19167"],"award-info":[{"award-number":["C588\/A19167"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C8216\/A6129"],"award-info":[{"award-number":["C8216\/A6129"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C588\/A10721"],"award-info":[{"award-number":["C588\/A10721"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms27062617","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T16:27:51Z","timestamp":1773332871000},"page":"2617","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genotype-Encoded UV Sensitivity in iPSC-Derived Human Melanocytes Reveals MX2 as a Physiological Amplifier of p53\/p38-Mediated DNA Damage Signaling"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0767-9357","authenticated-orcid":false,"given":"Eric","family":"Ramirez-Salazar","sequence":"first","affiliation":[{"name":"The Wistar Institute, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9770-2305","authenticated-orcid":false,"given":"Ana","family":"Slipicevic","sequence":"additional","affiliation":[{"name":"The Wistar Institute, Philadelphia, PA 19104, USA"},{"name":"Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, 0379 Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Juraleviciute","sequence":"additional","affiliation":[{"name":"Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, 0379 Oslo, Norway"},{"name":"Laser Research Center, Faculty of Physics, Vilnius University, LT-01513 Vilnius, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Li","sequence":"additional","affiliation":[{"name":"The Wistar Institute, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Harland","sequence":"additional","affiliation":[{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1588-6022","authenticated-orcid":false,"given":"Sally","family":"O\u2019Shea","sequence":"additional","affiliation":[{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sinead","family":"Field","sequence":"additional","affiliation":[{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Newton-Bishop","sequence":"additional","affiliation":[{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meenhard","family":"Herlyn","sequence":"additional","affiliation":[{"name":"The Wistar Institute, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/php.12377","article-title":"UV signature mutations","volume":"91","author":"Brash","year":"2015","journal-title":"Photochem. 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