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Review
. 2013 Jan 9;14(1):1132-51.
doi: 10.3390/ijms14011132.

The role of altered nucleotide excision repair and UVB-induced DNA damage in melanomagenesis

Timothy Budden  1 , Nikola A Bowden
Affiliations
Free PMC article
Review

The role of altered nucleotide excision repair and UVB-induced DNA damage in melanomagenesis

Timothy Budden et al. Int J Mol Sci. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Ultraviolet radiation spectrum: Ultraviolet radiation is composed of three wavelengths. UVA has the largest wavelength (315–400 nm), making it the least energetic, but UV at the earth’s surface is composed of 95% UVA. UVB (280–315 nm) composes approximately 5% of the UV on earth surface. UVC is the smallest wavelength (100–280 nm) and also the most energetic and toxic. UVC is absorbed by the ozone layer, and none reaches the surface of the earth.
Figure 2
Figure 2
Structure of DNA photoproducts caused by UVB radiation: Cyclobutane pyrimidine dimers (CPD) and 6-4 Photoproducts (6-4 PPs) are the most common UV induced mutations. (A) Chemical structures of cytosine (C) and thymine (T); (B) The chemical structure of a TC CPD. UVB radiation reacts with the double carbon bonds in the adjacent thymine bases and creates additional covalent bonds; (C) The structure of TC 6-4 PP. 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]).
Figure 3
Figure 3
The nucleotide excision repair pathway: There are two primary damage recognition paths in nucleotide excision repair. Global genome repair (GGR) functions across the entire genome, including non-coding and non-transcribed genes. Transcription coupled repair (TCR) acts with higher priority to repair actively transcribed genes. In GGR, the XPE complex and XPC sense UV lesions and act to recruit repair proteins. In TCR, RNA polymerase II is stalled at the UV lesion and CSA and CSB recruit repair proteins. Following damage recognition, both pathways converge on a single repair path in which the TFIIH complex unwinds the DNA around the damage site, by means of helicases XPB and XPD. XPA binds to the site of DNA damage, while RPA binds to the undamaged DNA and allows for binding of endonucleases XPF-ERCC1 and XPG, respectively, which cleave and excise the damaged strand. Following this, DNA polymerase and PCNA synthesize new DNA to replace the damage. The process is complete when DNA ligase seals the nicks between the old and new DNA.
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