Cell-intrinsic melanin fails to protect melanocytes from ultraviolet-mutagenesis in the absence of epidermal melanin

Tirzah J. Weiss, Emma R. Crawford, Valentina Posada, Hafeez Rahman, Tong Liu, Brandon M. Murphy, Tiffany E. Arnold, Shannon Gray, Zhexuan Hu, Rebecca C. Hennessey, Lianbo Yu, John A. D'Orazio, Craig J Burd, Jonathan H. Zippin, Douglas Grossman, Christin E Burd

Research output: Contribution to journalArticlepeer-review

Abstract

Melanin is a free-radical scavenger, antioxidant, and broadband absorber of ultraviolet (UV) radiation which protects the skin from environmental carcinogenesis. However, melanin synthesis and UV-induced reactive melanin species are also implicated in melanocyte genotoxicity. Here, we attempted to reconcile these disparate functions of melanin using a UVB-sensitive, NRAS-mutant mouse model, TpN. We crossed TpN mice heterozygous for an inactivating mutation in Tyrosinase to produce albino and black littermates on a C57BL/6J background. These animals were then exposed to a single UVB dose on postnatal day three when keratinocytes in the skin have yet to be melanized. Approximately one-third (35%) of black mice were protected from UVB-accelerated tumor formation. However, melanoma growth rates, tumor mutational burdens, and gene expression profiles were similar in melanomas from black and albino mice. Skin from albino mice contained more cyclobutane pyrimidine dimer (CPD) positive cells than black mice 1-h post-irradiation. However, this trend gradually reversed over time with CPDs becoming more prominent in black than albino melanocytes at 48 h. These results show that in the absence of epidermal pigmentation, melanocytic melanin limits the tumorigenic effects of acute UV exposure but fails to protect melanocytes from UVB-induced mutagenesis.

Original languageEnglish
Pages (from-to)6-18
Number of pages13
JournalPigment Cell and Melanoma Research
Volume36
Issue number1
DOIs
StatePublished - Jan 2023

Bibliographical note

Funding Information:
This work was supported by the Melanoma Research Alliance (309669 to C.E.B.), Damon Runyon Foundation (38‐16 to C.E.B., Pelotonia to E.R.C.), The National Institutes of Health (R01 CA237213 to C.E.B and V.P., R01 AR077664 to J.H.Z. and P30 CA016058 to The Ohio State University Comprehensive Cancer Center), and the Department of Dermatology at the University of Utah and the Huntsman Cancer Foundation (D.G.).

Publisher Copyright:
© 2022 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.

Keywords

  • UV radiation
  • carcinogenesis
  • dark CPD
  • melanin
  • melanocyte
  • mouse model

ASJC Scopus subject areas

  • Oncology
  • Biochemistry, Genetics and Molecular Biology (all)
  • Dermatology

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