Roles of UVA radiation and DNA damage responses in melanoma pathogenesis

Abstract

The growing incidence of melanoma is a serious public health issue that merits a thorough understanding of potential causative risk factors, which includes exposure to ultraviolet radiation (UVR). Though UVR has been classified as a complete carcinogen and has long been recognized for its ability to damage genomic DNA through both direct and indirect means, the precise mechanisms by which the UVA and UVB components of UVR contribute to the pathogenesis of melanoma have not been clearly defined. In this review, we therefore highlight recent studies that have addressed roles for UVA radiation in the generation of DNA damage and in modulating the subsequent cellular responses to DNA damage in melanocytes, which are the cell type that gives rise to melanoma. Recent research suggests that UVA not only contributes to the direct formation of DNA lesions but also impairs the removal of UV photoproducts from genomic DNA through oxidation and damage to DNA repair proteins. Moreover, the melanocyte microenvironment within the epidermis of the skin is also expected to impact melanomagenesis, and we therefore discuss several paracrine signaling pathways that have been shown to impact the DNA damage response in UV-irradiated melanocytes. Lastly, we examine how alterations to the immune microenvironment by UVA-associated DNA damage responses may contribute to melanoma development. Thus, there appear to be multiple avenues by which UVA may elevate the risk of melanoma. Protective strategies against excess exposure to UVA wavelengths of light therefore have the potential to decrease the incidence of melanoma. Environ. Mol. Mutagen. 59:438-460, 2018. © 2018 Wiley Periodicals, Inc.

Keywords: ATR kinase; DNA damage; DNA damage checkpoints; DNA damage signaling; DNA repair; Warburg effect; immune suppression; melanocytes; melanoma; nucleotide excision repair; skin cancer; ultraviolet A radiation; ultraviolet radiation.

Figure 1. Schematic for the chemiexcitation mechanism of CPD formation by UVA and melanin

UVA exposure form the sun or other sources leads to the generation of nitric oxide and superoxide within mammalian cells. These reactive species combine to form peroxynitrate, which can then act to degrade melanin (induced by UVA) into monomers and then act on fragments of melanin to produce an unstable but high energy (triplet state) dioxetane that reacts with DNA bases to form CPDs. These CPDs can form hours after UVA exposure and hence are referred to as “Dark CPDs”.

Figure 2. Schematics of major DNA repair systems that are utilized in UV-irradiated cells

Nucleotide excision repair (NER) system is the major DNA repair pathway that is utilized in UV-irradiated cells because of the high number of bipyrimidine dimers induced by UVR and takes place via a dual incision mechanism (involving the XPF and XPG endonucleases) that removes bipyrimidine dimers (indicated by a thymine dimer T<>T) from DNA in form of a small (~30-nt-long) oligonucleotide. DNA synthesis and ligation complete the repair reaction to restore the duplex to its native state (indicated in red). Base excision repair (BER) is utilized to repair oxidized base damage (such as 8-oxo-guanine [8-oxoG] residues) in UV-irradiated cells. BER involves a glycosylase that first removes the damaged base from the DNA before the action of AP Endonuclease, which incises the phosphodiester backbone 5’ to the apurinic (AP) site. DNA synthesis and ligation then restore the duplex. DNA double-strand breaks also form in UV-irradiated cells and can be repaired by either non-homologous end-joining (NHEJ) or homologous recombination (HR). NHEJ simply involves re-ligating two broken ends to one another without significant end processing. In HR, more extensive end processing and end resection takes place, which allows for strand invasion and pairing to homologous DNA sequence elsewhere in the genome. DNA replication allow for missing sequence to be synthesized before resolution of the HR intermediate and restoration of the DNA duplex.

Figure 3. DNA damage response kinases activated in UV-irradiated cells

The ATR, ATM, and DNA-PK protein kinases play pivotal roles in responding to various DNA damage signals in UV-irradiated cells. These kinases then initiate various signaling responses that may result in several different outcomes in the cells, including DNA repair, cell cycle arrest, modulation of DNA replication dynamics, altered gene expression, and cell death.