From DNA Repair to Proteome Protection: New Molecular Insights for Preventing Non-Melanoma Skin Cancers and Skin Aging
March 2014 | Volume 13 | Issue 3 | Original Article | 274 | Copyright © March 2014
Enzo Emanuele MD PhD,a James M. Spencer MD MS,b and Martin Braun MDc
aLiving Research sas, Robbio (PV), Italy
bMount Sinai School of Medicine, New York, NY
cVancouver, Canada
Abstract
Non-melanoma skin cancers (NMSC) are the most common human neoplasms and continue to represent an important public health issue with greater than one million cases diagnosed each year. The primary factor contributing to the molecular pathogenesis of NMSC is unprotected skin exposure to ultraviolet (UV) radiation, ie, UVA (wavelength: 315-400 nm) and UVB rays (wavelength: 280-315 nm) with additional albeit less damaging factors of infrared radiation (wavelength: ~750 nm -1 mm) and environmental pollutants. Skin carcinogenesis by DNA damage is the current predominant paradigm of UV toxicity, which may be caused by direct damaging effects of energy deposited by photons or indirect oxidative action of short-lived reactive oxygen species (ROS) formed from water that reacts with biomacromolecules. UV rays are capable to induce direct both DNA damages, mainly consisting in the formation of helix-distorting photoproducts such as cyclobutane pyrimidine dimers (CPDs), as well as oxidative damage to DNA bases, including the formation of 8-oxo-7, 8-dihydro-2’-deoxyguanosine (8OHdG). Growing evidence also suggests that the efficiency of DNA repair after exposure to UV radiation is crucially dependent on the levels of oxidative protein damage, including but not limited to DNA repair proteins. Besides DNA lesions, UV-induced oxidative stress can indeed result in carbonylation of proteins, a major form of irreversible protein damage that inactivates their biological function. Interestingly, microorganisms characterized by extreme resistance to UV rays have an intrinsic capacity to protect their proteome, rather than genome, from radiation-induced damage, suggesting that protein carbonylation (PC) may serve as a reliable and innovative biomarker of UV photodamage. This review discusses the main DNA and protein markers of UV-induced damage (eg, CPDs, 8OHdG, and PC) and their relationship and importance to the current understanding of skin carcinogenesis. The identification of key DNA and protein signatures of photodamage may represent a therapeutic target for translational studies of innovative therapeutic and preventive approaches for reducing both skin aging and the morbidity and mortality associated with NMSC.
J Drugs Dermatol. 2014;13(3):274-281.
INTRODUCTION
Non-melanoma skin cancers (NMSC) are the most common cancer worldwide and pose a significant and increasing burden on health care resources, with an estimated cost of $650 million and 2,200 American deaths each year.1 From an epidemiological standpoint, NMSC – comprising basal cell carcinoma and squamous cell carcinoma – account for at least 80% of all skin cancers.2,3 The incidence of NMSC has risen steadily over the last decade and this has been largely attributed to changes in the pattern of sun exposure of the population.4 It is universally established that exposure to ultraviolet (UV) radiation (ie, UVA and UVB rays with a wavelength of 315-400 nm and 280-315 nm, respectively) is the principal contributing factor to the development of NMSC by causing substantial damage to both DNA and proteins of the keratinocytes.5-8 Besides UV, other contributing albeit less damaging factors include infrared radiation (wavelength: ~750 nm -1 mm) and environmental pollutants. Evidence for the causative role of UV radiation in the pathogenesis of NMSC stems from 1) clinical observations, with the majority of NMSC appearing on photoexposed skin areas; 2) epidemiological evidence demonstrating an excess risk of NMSC in areas of high exposure to UV radiation; and 3) molecular findings showing the presence of UV-associated signature mutations in skin cancers.2
The initiation and progression of NMSC involves a complex series of molecular derangements. During this progression, cellular DNA damage and loss of cellular and enzymatic function due to protein oxidation are observed as cell phenotypes change from normal to aged skin, to actinic keratosis (AK), to superficial NMSC, and finally to metastatic disease.9 Importantly, the multiplicity of lesions at differing stages of development that can be generally observed in patients with NMSC reflects broad field molecular damage to the skin from UV radiation.10
