Dermatol Ther (Heidelb) (2019) 9:103–115 https://doi.org/10.1007/s13555-019-0282-5 REVIEW New Vision in Photoprotection and Photorepair Marie-Therese Leccia . Celeste Lebbe . Jean-Paul Claudel . Mridvika Narda . Nicole Basset-Seguin Received: November 21, 2018 / Published online: January 23, 2019 Ó The Author(s) 2019 ABSTRACT important in limiting further DNA damage. Several published studies have demonstrated Chronic exposure to solar radiation is associated the protective effect that regular use of sun- with an increased incidence of skin cancer screen can have against the development of worldwide and more specifically with non-me- skin cancers. Newer options that aim to help lanoma skin cancers and actinic keratosis. At repair damaged DNA may have an important the cellular level DNA damage is the main event role in reducing the incidence of chronic sun following ultraviolet (UV) exposure. The kind of exposure-related photoaging and non-me- lesions produced depends on the wavelength lanoma skin cancers. Photolyase, which is cap- and the energy profile of the radiation, with able of repairing cyclobutane dimers formed as different photoproducts being formed as a a result of DNA irradiation, is one such novel result. Although endogenous DNA repair ingredient. In the first part of this paper we mechanisms are somewhat effective in repairing review the rationale for a combined treatment DNA, some DNA damage persists and can approach of photoprotection and photorepair accumulate with chronic exposure. UV protec- with photolyase. In the second part we evaluate tion strategies, such as sunscreen use, are several published clinical studies, which suggest a beneficial effect in preventing new skin Enhanced Digital Features To view enhanced digital lesions in photodamaged skin. A strategy of features for this article go to https://doi.org/10.6084/ photoprotection plus photorepair appears to be m9.figshare.7584212. relevant for all persons with a high level of solar exposure and those at a higher risk for devel- M.-T. Leccia oping skin cancers. Service de Dermatologie, Centre Hospitalier Universitaire (CHU) de Grenoble, La Tronche, France C. Lebbe Á N. Basset-Seguin (&) Keywords: DNA repair; Photolyase; Skin Policlinique de Dermatologie, Hoˆpital Saint Louis, cancer; Sunscreen; Ultraviolet radiation Paris, France e-mail: [email protected] J.-P. Claudel INTRODUCTION Cabinet de Dermatologie, Tours, France The omnipresent nature of ultraviolet (UV) M. Narda radiation in our lives and increasing time spent Innovation and Development, ISDIN, Barcelona, Spain outdoors has led to a rise in UV-exposure related 104 Dermatol Ther (Heidelb) (2019) 9:103–115 pathologies. In a 2006 report, the World Health photoproducts (Fig. 1)[5]. A causal relationship Organization (WHO) estimated that around 1.5 has been established between UVB DNA lesions million disability-adjusted life years were lost and photocarcinogenesis, as indicated by the annually through the direct and indirect effects high proportion of p53 mutations characterized of excessive UV exposure worldwide [1]. Skin by cytosine (C)–thymine (T) transitions at cancer is the predominant pathological mani- dipyrimidine sites and CC–TT tandem base festation resulting from overexposure to UV substitutions detected at bipyrimidine sites in radiation, with non-melanoma skin cancers skin tumors [6]. Although less energetic than (NMSCs) representing more than 90% of all skin UVB, UVA is at least 20-fold more abundant in cancers. The WHO recently reported that up to natural sunlight and is equally involved in skin 2–3 million NMSCs are diagnosed worldwide carcinogenesis. The cytotoxic action of UVA each year, with the USA reporting up to 200,000 radiation is strongly oxygen dependent and new cases of squamous cell carcinoma (SCC) induces oxidative DNA lesions, mainly 8-oxo-7, annually, representing 20% of all new skin 8-dihydro-20-deoxyguanosine [7, 8]. However, cancers [1, 2]. Due to reporting requirements, UVA also induces large amount of CPDs in precise figures for NMSCs in Europe are difficult whole human skin through a mechanism which to ascertain, but the literature includes esti- differs from that triggered by UVB [9]. In con- mates of 78,000 cases annually in the UK, and trast to UVB, UVA preferentially induces the 41,000 in Germany [3]. New strategies to ame- production of CPDs at TT sites without any liorate the impact of chronic UV damage and detectable formation of 6-4PP photoproducts. thus skin cancers and photoaging are needed. Interestingly, the research group [9] showed in a This article is based on previously conducted subsequent study [10] that the rate of removal studies and does not contain any studies with of UVA-induced CPDs was lower than those human participants or animals performed by produced by UVB and that more UVA lesions any of the authors. were accumulated in whole skin, emphasizing the crucial role of UVA in skin carcinogenesis. UVA photons are partly absorbed by the upper UV-MEDIATED SKIN DAMAGE layers of skin, yet they are also able to penetrate deep into the dermis, whereas UVB radiation is Chronic exposure to solar radiation is the most mostly absorbed by the epidermis. The limited important environmental factor involved in capacity of human skin to repair UVA-induced photoaging and in the pathogenesis of skin cancers, especially actinic keratosis (AK) and SCC. The role of UV radiation in the patho- genesis of basal cell carcinoma (BCC) and mel- anoma appears more complicated, but is probably related to acute exposure during childhood and adolescence. Cellular DNA is the major cellular target in UV carcinogenesis, through the induction of photo-induced direct and indirect damage that can induce mutations [4]. The chemical nature and the formation of DNA lesions greatly depend on the wavelength of incident photons. UVB radiation, the most energetic and muta- genic component of solar radiations, is directly absorbed by DNA and induces dimeric photo- Fig. 1 Ultraviolet (UV) radiation-induced changes ulti- products between adjacent pyrimidine bases, mately lead to non-melanoma skin cancers (NMSC). CPD namely cyclobutane pyrimidine dimers (CPDs) Cyclobutane pyrimidine dimer, 6–4PP pyrimidine (6–4) and pyrimidine (6–4) pyrimidone (6-4PP) pyrimidone Dermatol Ther (Heidelb) (2019) 9:103–115 105 DNA damage is responsible for the accumula- burden with the progression from normal UV- tion of UVA-induced DNA lesions in the whole exposed skin to AK and then to SCC [19]. The human skin. development of skin SCCs involves a large The role of unrepaired DNA lesions comes number of chromosomal aberrations, with the into play when these stereochemically most significant of mutated genes being TP53, unwieldy alterations lead to replication errors NOTCH1-2, FAT1, MLL2 and KNSTRN [20–24]. that result in mutations. Although the majority In contrast, BCCs arise with no established of spontaneously occurring mutations that precursor and present with a high mutation accumulate in somatic cells throughout a per- rate. A high prevalence of UV signature. BCCs son’s lifetime may go unnoticed without having are driven by the Sonic Hedgehog (Hh) path- any major effects, some can alter key cellular way, with a high frequency of mutations of functions, leading to cancer and aging [11]. PTCH1 (73%), SMO (20%) and SUFU (8%). Other Different mutations might evolve differently in less frequently altered driver genes include sun-exposed skin depending on clonal expan- TP53, MYCN, PPP6C, STK19 LATS1, ERBB2, sion and the positive selection of the cells PIK3CA and the RAS family [25–29]. involved. At any given time sun-exposed skin Due to their high prevalence, NMSCs are has been described as a patchwork of thousands altogether among the five most expensive can- of evolving clones with over one-quarter of the cer diseases according to the Medicare Benefi- cells carrying cancer-causing mutations while ciary Survey 1992–1995 (Medicare being the maintaining the physiological functions of the health-insurance provider for Americans epidermis [11]. Loss of p53-induced protective administered by the US government) [30]. mechanisms results in the accumulation of Recent temporal trends investigated in Aus- additional mutations and chromosome insta- tralia, Canada and the USA indicated a more bility, culminating in abnormal keratinocyte than twofold increase in NMSC prevalence, as proliferation and resulting in a gradual upreg- well as a higher frequency on sun-exposed ulation of the pre-tumorigenic (AK) and areas, implicating long-term, repeated UV radi- tumorigenic (SCC) lesions when compared to ation exposure as a major causal factor. Some normal skin and non-tumorigenic lesions [12]. countries also report an association between increasing incidences of NMSCs with decreasing latitude, i.e. higher UV radiation levels [13]. UV AND NMSC When UV protection strategies are being developed, high-risk populations must be given Worldwide, NMSC incidence ranges from the special consideration. Risk factors include Fitz- highest rates in Australia ([ 1000/100,000 per- patrick skin type I to III, baldness, male gender, son-years for BCC) to the lowest rates in parts of older age, precancerous skin conditions (AK and Africa (\ 1/100,000 person-years for BCC). In Bowen’s disease), immune deficiency and the Europe the highest incidence rates for BCC and frequent use of sunbeds [31]. A higher lifetime SCC have been reported in the UK [13]. In exposure to the sun or other sources of UV France, BCC and AK represent 1 and 5% of radiation is clearly associated with a higher dermatological consultations, respectively [14]. incidence of SCCs and BCCs. Outdoor workers Sixty percent of SCC arise from a lesion diag- run a significantly increased risk for developing nosed clinically as a solar keratosis in the pre- NMSCs [32]. A recent analysis of the European vious year [15]. The relative risk of malignant multi-center EPIDERM study showed a fourfold transformation of a pre-existing AK lesion is 2.2- increased odds of developing AK among out- fold higher than the risk of SCC in normal skin door workers, with the risks increasing with [16].