Abstract
UVB radiation is the most mutagenic component of the UV spectrum that reaches the earth’s surface and causes the development of DNA damage in the form of cyclobutane pyrimidine dimers and 6-4 photoproducts. UV radiation usually results in cellular death, but if left unchecked, it can affect DNA integrity, cell and tissue homeostasis and cause mutations in oncogenes and tumour-suppressor genes. These mutations, if unrepaired, can lead to abnormal cell growth, increasing the risk of cancer development. Epidemiological data strongly associates UV exposure as a major factor in melanoma development, but the exact biological mechanisms involved in this process are yet to be fully elucidated. The nucleotide excision repair (NER) pathway is responsible for the repair of UV-induced lesions. Patients with the genetic disorder Xeroderma Pigmentosum have a mutation in one of eight NER genes associated with the XP complementation groups XP-A to XP-G and XP variant (XP-V). XP is characterized by diminished repair capacity, as well as a 1000-fold increase in the incidence of skin cancers, including melanoma. This has suggested a significant role for NER in melanoma development as a result of UVB exposure. This review discusses the current research surrounding UVB radiation and NER capacity and how further investigation of NER could elucidate the role of NER in avoiding UV-induced cellular death resulting in melanomagenesis.
Highlights
It has been long known that solar radiation is genotoxic, with UV radiation being the most mutagenic component [1]
DDB2 gene has shown that it contains a region that binds p53 to control transcription [89]. These results show that p53 directly controls DNA damage repair after UV damage through the expression of global genome repair (GGR) genes XPC and DDB2 (XPE) and that wild-type p53 expression is important for efficient GGR repair
The exact molecular mechanisms of the link between UV and melanoma are not completely understood, but a possible link is evident in the genetic disorder Xeroderma Pigmentosum (XP) in which the dysfunction of the nucleotide excision repair (NER) pathway directly results in UV-induced skin cancers
Summary
It has been long known that solar radiation is genotoxic, with UV radiation being the most mutagenic component [1]. UVB remains the most mutagenic component of terrestrial UV, due to the fact that it is directly absorbed by DNA While it is less abundant than UVA, it is absorbed by DNA more efficiently, with a tenfold difference between the two wavelengths. A single covalent bond forms between a double carbon bond and a carbonyl group in adjacent pyrimidines, linking the two bases; (D) The additional bonds in both of these lesions result in a bulky adduct that affects the double helix structure of DNA, which can halt transcription and DNA replication (Image adapted from [2]). 6-4 Photoproducts (6-4 PPs) are formed when UV reacts with the carbonyl group and double carbon bond in adjacent pyrimidines This leads to an excited state and unstable oxetane, which is spontaneously rearranged to form a 6-4 PP [1]. It is hypothesised that CPDs containing cytosine are susceptible to spontaneous deamination, which results in a C>T or CC>TT transition
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