Endothelin‐1 and α‐melanocortin have redundant effects on global genome repair in UV‐irradiated human melanocytes despite distinct signaling pathways

Abstract

Human melanocyte homeostasis is sustained by paracrine factors that reduce the genotoxic effects of ultraviolet radiation (UV), the major etiological factor for melanoma. The keratinocyte‐derived endothelin‐1 (End‐1) and α‐melanocyte‐stimulating hormone (α‐MSH) regulate human melanocyte function, proliferation and survival, and enhance repair of UV‐induced DNA photoproducts by binding to the Gq‐ and Gi‐protein‐coupled endothelin B receptor (EDNRB), and the Gs‐protein‐coupled melanocortin 1 receptor (MC1R), respectively. We hereby report that End‐1 and α‐MSH regulate common effectors of the DNA damage response to UV, despite distinct signaling pathways. Both factors activate the two DNA damage sensors ataxia telangiectasia and Rad3‐related and ataxia telangiectasia mutated, enhance DNA damage recognition by reducing soluble nuclear and chromatin‐bound DNA damage binding protein 2, and increase total and chromatin‐bound xeroderma pigmentosum (XP) C. Additionally, α‐MSH and End‐1 increase total levels and chromatin localization of the damage verification protein XPA, and the levels of γH2AX, which facilitates recruitment of DNA repair proteins to DNA lesions. Activation of EDNRB compensates for MC1R loss of function, thereby reducing the risk of malignant transformation of these vulnerable melanocytes. Therefore, MC1R and EDNRB signaling pathways represent redundant mechanisms that inhibit the genotoxic effects of UV and melanomagenesis.

UVB mutagenesis differs in NRAS- and BRAF-mutant mouse models of melanoma

“…A reduction in the activity of one or several of these components may compromise photoproduct repair in UVA-irradiated cells and explain why UVA-induced CPDs take longer to resolve 36 . UVB damage also causes keratinocytes to produce paracrine factors like α-Melanocyte Stimulating Hormone (αMSH) and Endothelin-1 (End-1), which activate ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR), resulting in a DNA damage response which could enhance the recognition and repair of UV photolesions 40 .…”

Participation of keratinocyte‐ and fibroblast‐derived factors in melanocyte homeostasis, the response to UV, and pigmentary disorders

“…These results suggest that the tanning response to UVB is modulated by keratinocyte‐derived factors. It is established that α‐MSH, and by analogy ACTH, via activation of MC1R and its cAMP signaling pathway, modulates the DNA damage response (DDR) of melanocytes (Bohm et al., 2005; Kadekaro et al., 2010; Swope et al., 2014, 2020). α‐MSH and ACTH are survival factors for melanocytes, as they reduce melanocyte apoptosis resulting from extensive UVB‐induced DNA damage.…”

The α‐melanocyte‐stimulating hormone/melanocortin‐1 receptor interaction: A driver of pleiotropic effects beyond pigmentation

“…MC1R allelic variants hypomorphic for the cAMP pathway were not able to activate this DNA damage response (Swope et al., 2014). One year later, another research group demonstrated that cAMP‐dependent PKA activation induced by α‐MSH/MC1R led to ATR phosphorylation at Ser435, which actively recruited XPA to sites of nuclear UVR photodamage, promoting clearance of UVR‐induced photolesions and reducing mutagenesis (Jarrett et al., 2014, 2015; Swope et al., 2020). Moreover, MC1R activation by α‐MSH was shown to result in a rapid and transient induction of all three family members of the nuclear receptor subfamily 4 (NR4A), which was impaired in melanocytes that were homozygous for MC1R RHC variant alleles (Smith et al., 2008).…”