Unravelling UVA-induced mutagenesis

Abstract

Ultraviolet A (UVA) radiation represents more than 90% of the solar UV radiation reaching Earth's surface. Exposure to solar UV radiation is a major risk in the occurrence of non-melanoma skin cancer. Whole genome sequencing data of melanoma tumors recently obtained makes it possible also to definitively associate malignant melanoma with sunlight exposure. Even though UVB has long been established as the major cause of skin cancer, the relative contribution of UVA is still unclear. In this review, we first report on the formation of DNA damage induced by UVA radiation, and on recent advances on the associated mechanism. We then discuss the controversial data on the UVA-induced mutational events obtained for various types of eukaryotic cells, including human skin cells. This may help unravel the role of UVA in the various steps of photocarcinogenesis. The connection to photocarcinogenesis is more extensively discussed by other authors in this issue.

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Introduction

The ultraviolet (UV) portion of sunlight is divided into UVC (below 280 nm), UVB (280–315 nm) and UVA (315–400 nm). This division allows the ranking of the effects of solar exposure on living species. Wavelengths below 290 nm are blocked by the stratospheric ozone. These wavelengths are of the highest energies (>4.4 eV), coinciding with maximal absorption by DNA and other biomolecules, and are extremely damaging to genetic material and biological tissues in general. Therefore the stratospheric ozone layer protects life from UVC radiation. Longer wavelength UVB (λ > approximately 290 nm) penetrates the ozone layer and constitutes 5–10% of the terrestrial solar UV radiation. It is absorbed by nucleic acids and consequently has the ability to directly cause genotoxic damage to DNA and ultimately cause skin cancer.

Radiation in the UVA range is by far the most abundant solar UV radiation (above 90%) that reaches the surface of earth. It is associated with low energies (3.1 to 3.9 eV). UVA radiation also penetrates human skin more effectively than UVB. Unlike UVB, the UVA component of solar radiation is weakly absorbed by DNA,¹ but instead excites other endogenous chromophores, generating various reactive oxygen species (ROS) in cells. Moreover, most UVA-mediated biological events are oxygen-dependent. These observations provided the basis for considering UVA as a strong generator of oxidative stress. Singlet oxygen is the major ROS involved in UVA-mediated cell inactivation and gene activation, it is also a primary source of UVA-mediated signalling.^2–4

Once thought to be relatively innocuous, UVA is now known as a damaging agent for DNA, proteins, and lipids, with harmful consequences such as skin ageing and carcinogenesis. Exposure of the human population to UVA has significantly increased in the last decades. This is due to the popularity of UVA tanning salons and to the widespread use of efficient UVB-absorbing sunscreens which block erythema, allowing prolonged periods of sunbathing. As a consequence, the deleterious effect of UVA has recently emerged as a source of concern for public health. For example, sunbeds, which principally emit in the UVA range, have been included into the list of human carcinogens by the International Agency of Research on Cancer.⁵ The cellular and molecular responses to UVA in relation to skin carcinogenesis have been recently reviewed.⁶ The present review focuses on the formation of DNA damage, its possible underlying mechanisms and on mutagenesis induced by UVA radiation.

1. Formation of DNA damage by UVA and underlying mechanisms

Through direct absorption by DNA, UVC and UVB radiation cause the formation of cyclobutane pyrimidine dimers (CPDs), pyrimidine (6–4) pyrimidone photoproducts (6–4PPs) and their Dewar valence isomers. These bipyrimidine photoproducts were not expected to be formed by UVA because of the inability of DNA to readily absorb in the UVA range. Meanwhile, a pioneering work from Tyrrell's group reported the induction of CPDs in bacteria by very pure narrow-band 365 nm UVA, with a higher relative frequency of TT CPDs and a reduced excision of these CPDs compared to 254 nm UVC.^7,8 It has long been known that UVA promotes photosensitization of DNA, triggered by singlet oxygen (type II photosensitization), electron abstraction (type I photosensitization) or hydroxyl radicals. Early reports showed the induction of single strand beaks (SSB, in fact alkali-labile sites) in UVA-irradiated bacteria, phage DNA and mammalian cells, in addition to DNA-protein crosslinks.^9,10 Since the 1990s, new and sensitive methods have been available for the efficient measurement of various types of DNA lesions and UVA-induced DNA damage has been reassessed.

Altogether, more recent studies show that UVA radiation induces single strand breaks (SSB), oxidized pyrimidine and purines in various mammalian cell lines.^11–16 The most abundant oxidative DNA damage produced is 8-oxoguanine (8oxoG).^17–19 The low amounts of SSB and oxidized pyrimidines, likely produced by hydroxyl radicals originating from Fenton reaction, in addition to the predominance of 8oxoG, signal a major contribution of singlet oxygen in the formation of oxidative DNA damage in mammalian cells.²⁰

Upon UVA exposure, CPDs are detected in mammalian cells, and in human and mouse skin as well,^{11,13,14,17,19,21–28} while produced at low yield in comparison with 254 nm UVC.^7,23 Using a broad band UVA source, we calculated that 500 kJ m⁻²UVA is necessary to produce the same amount of CPDs as 5 J m⁻² 254 nm UVC.²³ Interestingly, CPDs are detected at UVA doses as low as 40 kJ m⁻², and at such low doses CPDs are still about 2 times more frequent than 8oxoG (Sage, Girard, Douki, unpublished). In agreement with the original studies in bacteria,⁷ the distribution of CPDs induced by UVA drastically differs from that produced by UVC, UVB or simulated sunlight (SSL). UVA-induced CPDs predominantly form at TT sites, while those produced at CC sites are poorly represented.^19,25,27

6–4 photoproducts have not been significantly detected in mammalian cells after UVA^14,19,23 although they are possibly produced.²⁹ Moreover, UVA radiation is able to photoisomerize 6–4 photoproducts produced by the UVB photons of simulated sunlight into Dewar photoproducts.^19,23 This supports the observation that Dewar photoproducts are more frequently produced by natural and simulated sunlight than by UVB.^23,30DNA double strand breaks, revealed by neutral comet assay or γ-H2AX (phosphorylated H2AX variant histone) foci, are not readily produced in human transformed fibroblasts or keratinocytes by direct UVA irradiation, but likely occur at low extent during the process of repairing DNA lesions.^31,32 In addition, UVA slows down S phase and induces accumulation of Rad52 foci, indicating that genome integrity is challenged.^32,33

Evidence recently emerged in favour of a direct absorption of UVA by DNA to mediate CPD formation. Firstly, the distribution of the different types of DNA damage induced by UVA is similar in plasmid or isolated DNA and in cells.^29,34–37 Indeed, upon UVA irradiation, CPDs are formed in plasmid DNA by a mechanism that should not involve photosensitization reactions, due to the absence of photosensitizer in the irradiation mixture. Therefore, CPDs in plasmid or isolated DNA is likely to be formed by direct absorption. Moreover, it has clearly been demonstrated that UVA radiation is able to induce 6–4PPs in plasmid DNA,²⁹ while 6–4PPs are produced in tiny amount in cells.²³ Importantly, the formation of 6–4PPs by photosensitization has never been reported and it is generally assumed that they are only produced by direct absorption. Finally, another argument is provided by the similarities in the yields of CPD formation within calf thymus DNA and keratinocytes exposed to UVA through filters exhibiting increasing cut-off wavelengths (322–390 nm).³⁶ Collectively, these observations strongly suggest that the photochemical process underlying the formation of CPDs by UVA is direct absorption of UVA photons by DNA. The low energy of UVA photons is sufficient to directly excite DNA bases (at least thymine)³⁸ with subsequent formation of bipyrimidine photoproducts, both CPDs and 6–4PPs, albeit at low levels. The predominance for CPD formation at TT sites may be explained by the fact that thymine has, in fact, the lowest triplet state energy with regard to other bases. In contrast, 8-oxoG is essentially formed by photosensitization reaction mediated by singlet oxygen.

2. UVA-induced mutagenesis in eukaryotic cells and skin

The UVB mutational signature has been well defined as C to T transitions at bipyrimidine sites and tandem CC to TT mutations.³⁹ It is mostly mediated by CPDs in repair-proficient cells/individuals.⁴⁰ It has been found in a large majority of non-melanoma skin tumours,^39,41 and, recently, through a genome-wide analysis, in malignant melanoma as well.^42,43 It is now established that the two major known photolesions induced by UVA radiation are CPDs and 8-oxoG, the ratio of which presumably depends on irradiation conditions, cell and skin types, and individuals. However, the relative contribution of bipyrimidine photoproducts or 8oxoG to the mutagenic and cytotoxic effects of UVA exposure remains a topic of active debate.⁴⁴ Moreover, the relative contribution of UVA radiation to solar mutagenesis and skin cancer is still an open question.

From most of the studies it appears that UVA radiation is weakly mutagenic at environmentally relevant doses, while it is cytotoxic in mammalian cells, yeast and Drosophila larvae.^15,45–48 Studies in the yeast Saccharomyces cerevisiae show that the cytotoxicity of UVA does not depend on DNA damage.⁴⁷ It is probable that cytotoxicity of UVA is mostly due to ROS-induced damage to other constituents, particularly proteins and membrane lipids.

In an early work, Drobetsky et al. observed a predominance of AT to CG transversions in the UVA-induced mutation spectrum in Chinese Hamster Ovary cells.⁴⁵ Those mutations, in fact, correlate with sites of UVA-induced TT CPDs.²⁵ However, such mutations could also be caused by incorporation of 8oxodGTP (from dNTP pools oxidized by UVA) opposite adenine by replicative DNA polymerase. In the absence of nucleotide excision repair, the mutation frequency is increased 7-fold and the spectrum is largely dominated by C to T transitions.⁴⁹ Among point mutations in transformed human embryonic kidney cells⁵⁰ or in cultured primary human fibroblasts,⁵¹C to T transitions at bipyrimidine sites are the predominant events. On the other hand, in all these studies, G to T transversions, the so-called hallmark of 8oxoG,⁵² are barely recovered. In addition, the ogg1−/− mouse embryonic fibroblasts, that are unable to repair 8oxoG, do not exhibit an increase in mutation induction in comparison with the OGG1+/+ counterpart, after exposure to UVA or UVB.⁵³ Altogether, this series of data is not consistent with a prominent role for 8oxoG in UVA-induced mutagenesis, but rather points out CPDs.

Pfeifer and collaborators using Big Blue mouse embryonic fibroblasts, claim that 8oxoG is the major cause for UVA mutagenesis.^14,15,48,54 Indeed, in their hands, G to T transversions represent 26–28% of the total mutations. Small deletions are also observed. However, the most frequent events (30–40% of total) were C to T transitions occurring at bipyrimidines. This class of mutation was excluded by the statistical analysis, since it is also observed in unirradiated cells, albeit at a 2- to 3-fold lower frequency. Examining the sites of mutations, it appears that most of the C to T transitions induced by UVA, except for one hot-spot that could be of spontaneous origin, occur at sites different from that of the spontaneous C to T transitions. Moreover, parts of them are recovered at sites which are also UVB mutational hotspots. It should be noted that, in contrast to all the other studies, cell irradiation was performed in the presence of culture medium that contained high concentration of a well-known photosensitizer, riboflavin, so that the elevated frequency of G to T transversions may be explained by a prominent production of 8oxoG by photosensitization viariboflavin.⁵⁵ Interestingly, in yeast, oxidative DNA damage, in particular 8oxoG, undoubtedly plays a major role in the UVA-induced mutations, as demonstrated using DNA-repair deficient strains and analysis of DNA damage production.⁴⁷ The G to T transversions represent 40% and 28% of the mutational events upon UVA and simulated sunlight exposure, whereas only 12% upon UVC irradiation in Saccharomyces cerevisiae.^47,56 These studies in yeast which used a large variety of DNA repair and translesion synthesis mutant strains represent the most extensive mutational analysis performed in eukaryotic cells. It has also been proposed that, besides CPDs, more complex DNA lesions play a role in UVA-induced mutagenesis, at least in hamster cells.⁵⁷ All these diverse observations obtained with acute doses on various cultured cells indicate that classes of mutations induced by UVA greatly depend on the cell types. It is elusive to define precisely the effect of UVA on human skin cells, at least from a mutational point of view.

UVA-induced tumors in hairless mice exhibit a low incidence of p53 mutations and all mutations were C to T transitions, mostly occurring at sites of UVB mutational hotspots.⁵⁸ The most extensive analysis of mutations induced in skin has been performed in mice by Ikehata et al., using 364 nm UVA1 laser light, in comparison with UVB and sunlight.⁵⁹ It was found that 65% of the total mutants recovered in the UVA-irradiated epidermis carry C to T transitions, 90% of which occurred at bipyrimidine sites. In contrast, G to T transversions, possibly originated from 8oxoG, represent only 6% of total mutations in UVA- or sunlight-irradiated epidermis, and no T to G transversions are found.⁵⁹ The UVA-induced mutation spectrum differs somewhat from that induced by UVB. It is characterized by a high frequency of C to T mutations at 5′-TCG-3′ sequences where CpG is methylated at the cytosine residue, a feature which is less pronounced after UVB or sunlight exposure. As expected, UVB contributes much more than UVA to the sunlight-induced mutation spectrum.^59,60 Remarkably, the authors calculated that the UVA component of sunlight would provoke a 3-fold induction of mutations after a whole day of sun exposure, while UVB or sunlight would cause 15-fold and 35-fold mutation induction after an hour exposure at noon. The genotoxicity of UVA is indeed much smaller than that of UVB. However, these results cannot be directly applied to the human situation to predict UVA genotoxicity and risk to health, since human skin is much thicker than mouse skin and, in reality, the human population is exposed to multiple doses rather than single doses of UVB or UVA.

Very limited data are available on the mutations induced by UVA in human skin. Persson et al. analyzed p53 mutation in individual human skin keratinocytes repeatedly exposed to UVA and found three p53 mutated cells, all with a G to T tranversion.⁶¹ Engineered human skin was exposed four times to UVA, UVB or a mixture which resembled sunlight, and p53 mutations were recovered in all cases.⁶²UVA led to a predominance of mutations in the basal epidermis which contains dividing keratinocytes and is thought to give rise to skin cancer. The low number of mutations observed and the presence of a strong mutational hotspot in UVA-irradiated samples do not allow further conclusions at the molecular level. However, the data did confirm an earlier report that UVA and UVB contribute to sunlight-induced p53 mutations in human skin tumours.⁶³ It is worth mentioning that GC to TA transversion is not exclusively the mutational signature of 8oxoG, but can also be induced by other genotoxic agents, such as polycyclic aromatic hydrocarbons.⁶⁴ Skin has a protective function, and is exposed to environmental pollutants. To what extent those carcinogens penetrate the epidermis and generate mutations, either directly or through photosensitization reaction and ROS induction, is not yet well established. At least, from this chapter, it should be stated that C to T transition at bipyrimidine sites is a UV signature and not specifically a UVB (or UVC) fingerprint.

3. DNA repair and persistent genome instability induced by UVA in mammalian cells

The UVA-induced DNA lesions are repaired with different kinetics. The 8oxoG is efficiently and quickly eliminated within 3–6 h by base excision repair in mammalian cells, and is not expected to lead to extensive mutations in repair-proficient cells. The 6–4PPs are efficiently repaired by nucleotide excision repair and eliminated within 6 h, while a fraction of CPDs still persist 24 h after exposure. In addition, UVA may slightly compromise the repair of bipyrimidine photoproducts.²⁷ Interestingly, human 8-oxoguanine-DNA glycosylase 1 protein and gene are expressed more abundantly in the superficial than basal layer of human epidermis.¹⁶ This may lead to a lack of repair in the basal cells of the epidermis and therefore to accumulation of mutations due to 8oxoG. It has also been reported that the repair rate of CPDs over 24 h period after UVC or UVB irradiation was substantially the same in cultured human skin keratinocytes or melanocytes and that melanocytes and melanoma cells harbor similar nucleotide excision repair capacity.^65,66 Meanwhile, melanocyte cell extracts have been shown to be partially defective in repair of oxidative DNA damage and UVC-induced photoproducts, in comparison with human skin fibroblasts.⁶⁷

There is increasing evidence for long-term consequences of UVA exposure. These long-term changes may lead to cells that can eventually acquire a hypermutator phenotype and later carcinogenic potential. For example, UVA produces fewer immediate mutations but more delayed mutations several generations post-irradiation, which are associated with ROS formation, than UVB or X-rays, in Chinese hamster fibroblasts.⁶⁸ In addition, UVA is able to induce large deletions as a consequence of both immediate or delayed mutations.⁶⁹UVA exposure of human HaCaT transformed keratinocytes leads to a continuous reduction of cell survival and to an increase in mutations and in micronuclei formation up to 21 days post-irradiation.⁷⁰ In the same cell line, long-lasting DSB may be responsible for the appearance of micronuclei and chromosomal aberrations, and may confer tumorigenic phenotype.³¹ Notably, UVA also induces a dose-dependent telomere shortening, possibly correlated with a targeting of 8oxoG formation in the GC-rich telomeric sequences.⁷¹ This last event could be a cause of skin ageing;⁷² an implication in skin cancer requires further investigation.⁷³ A recent report has established that human telomeres are particularly hypersensitive to UV(C)-induced CPDs and refractory to repairing these DNA lesions, in primary human fibroblasts.⁷⁴ However, chronic UVC irradiation does not accelerate telomere shortening. Due to a difference of sequence specificity in CPD formation with UV wavelength, the propensity of UVA to damage human telomeres (repeats of 5′TTAGGG/5′CCCTAA) may be in favour of 8oxoG formation. The telomere shortening observed after UVA exposure could be due to DSBs generated as repair intermediates at clustered 8oxoG. This remains to be investigated.

4. A role for UVA in the initial steps of cutaneous carcinogenesis

There are clues in favour of, but no absolute proof of, a role of UVA in skin cancer. UVA damages DNA and is mutagenic at environmentally relevant doses, inducing CPDs, 8oxoG and other lesions. The absolute yield of CPD formation by UVA is about 10³ times lower than that by filtered broad band UVB.^19,23 From a mean solar spectral emission and the action spectrum for CPDs formation in ref. 17, it is estimated that about 10% of CPDs produced by sunlight could be initiated by UVA photons.⁷⁵In vitro studies showed that a UVA mutational signature can be observed in sunlight-induced mutation spectra in various biological systems, even though the UVB component largely predominates.^{15,45,47,56,59,60} The fact that skin is exposed to about 100 times more UVA than UVB and that UVA penetrates more efficiently into skin layers suggests that a fraction of CPDs formed at the basal layer in skin may be produced by UVA. Indeed, consecutive to analysis of p53 mutations and on the presence of CPDs and 8oxoG in biopsies from squamous cell carcinomas (SCC) and excised premalignant solar keratosis (SK), Agar et al. conclude that the basal layer in tumours harbors more mutations with an UVA rather than UVB fingerprint.⁶³ This is based on a UVB fingerprint defined as C to T transitions at bipyrimidine sites, which is found primarily in keratinocytes of the stratum granulosum in SCC and SK, and on the events matching an UVA fingerprint, defined as T to G and G to T mutations, which are more abundant in the basal layers. In addition, CPDs are detected throughout the epidermis but are maximal in the upper layers, while 8oxoG detection exhibits a bias towards basal layers in all SK and SCC. This appears consistent with the higher penetration of UVA down to the basal epithelial layers and dermis, whereas the penetration of short-wavelength UVB is confined predominantly to the superficial epidermis. However, such conclusions can be questioned, since both UVB and UVA induce CPDs formation and give rise to C to T transitions and that 8oxoG and G to T transversions can also be produced by UVB at low extent. Even though the mutational specificity of UVA is not yet clearly established, in particular in skin cells and tissue, these data strongly suggest a possible role for UVA in human skin carcinogenesis.⁷⁶

UVA radiation has been shown to induce skin carcinomas in mice.⁷⁷ The role of UVA in melanoma has been a subject of intense debate and several reviews (ref. 78–80, and Mitchell and Fernandez in this issue⁹⁴), since Setlow et al.⁸¹ reported that UVA is able to cause melanoma in pigmented platyfish Xiphophorus. Reexamining the induction of melanoma by UVA in Xiphophorus hybrid model, Mitchell et al. could not confirm the original data.⁸² Ley showed that prolonged UVA exposure, but not UVB, can induce melanocytic hyperplasia (melanoma precursor) in pigmented opossum Monodelphis domestica.⁸³ On the contrary, UVB, but not UVA, can induce malignant melanoma in engineered transgenic mice.⁸⁴ In fact, virtually none of the animal models developed exhibit susceptibility to melanoma induction by UVA. The recent and important report by Mitchell refutes the only direct evidence that UVA causes melanoma.⁸² However, several recent epidemiological studies show positive relationship between melanoma incidence and use of sunbeds (ref. 85, and Doré and Chignol in this issue⁹⁵). This does not indicate a sole implication of UVA since sunbeds have highly variable emission spectra and emit UVB to various extent.

With regard to the protection from skin cancer and particularly from melanoma by melanin, the fair-skinned population exhibits a higher incidence of melanoma than dark-pigmented individuals. Beside genetic predisposition, pheomelanin and eumelanin present in fair skin can act as photosensitizers and produce ROS, but eumelanin which is more abundant in dark skin, exhibits a higher ratio of protection to photosensitization than pheomelanin and insures a better protective effect against solar radiation to dark-skinned population.^86–88 In this respect, human melanoma cells with high melanin content accumulate two times more 8oxoG after UVA irradiation than cells with low melanin content.⁸⁹ In addition, it has been reported that melanocyte extracts are partially defective in the repair of oxidative DNA damage and UVC-induced CPDs and 6–4 photoproducts in comparison with normal human skin fibroblasts and lightly pigmented melanocytes have a lower repair capacity for photoproducts than darkly pigmented melanocytes.⁶⁷ The mutational signature of UV exposure and the low frequency of GC to TA mutations in the genomes of malignant melanoma exclude a strong involvement of ROS in the development of melanoma, but do not eliminate a UVA contribution.^41,43

5. Mitochondrial mutagenesis and photoageing

Compared to the nuclear genome, mitochondrial DNA (mtDNA) accumulates mutations, partly due to the lack of protective histones and the absence of nucleotide excision repair, but mainly caused by the deleterious effect of ROS issued from electron leaking from the respiratory chain and reacting with oxygen. In terms of DNA repair, mitochondria possess functional base excision repair, double strand break repair and mismatch repair, pathways which are essential to protect mtDNA from extensive damaging effect of ROS. Large mtDNA deletions (3–10 kbp) can be detected in many human tissues, at high levels in nonreplicating tissues, and at a lower extent in slowly replicating tissues. Normal human skin, as a replicating tissue, carries a low amount of mtDNA deletions. The accumulation of mtDNA deletions has been proposed as an underlying cause of the ageing process. The use of mtDNA damage has been introduced as a biomarker for cumulative sun exposure in human skin and skin photoageing (reviewed in ref. 90 and 91). The most frequent event, a 4977 bp deletion, is more frequent in chronically sun-exposed skin than in sun-protected skin. Early studies using normal human fibroblasts assess a role of UVA and ROS, in particular singlet oxygen, in the generation of the photoageing-associated common deletion,⁹² which can be prevented by supplementation with betacarotene, a known ROS and singlet oxygen quencher, or with creatine, the ATP-producing precursor.⁹³ The role of mitochondria and mtDNA mutagenesis in photoageing and photocarcinogenesis could be related to mitochondrial functions in the bioenergetic system and in apoptosis.

Conclusion

UVA elicits a biologically significant amount of CPDs and 8oxoG at environmentally relevant doses, while UVB produces CPDs to a larger extent. UVA is a relatively weak mutagen, in agreement with a low induction of DNA damage. In contrast to CPDs, which may persist, 8oxoG is rapidly and efficiently repaired and contributes very poorly to solar UV mutagenesis. The current knowledge attributes a prominent role to CPDs in the initiation of non-melanoma skin cancer, and likely of melanoma too (at least those in sun-exposed skin). UVA could be involved in the initiation of the skin cancers in the human population, at least in case of heavy exposure to UVA, i.e. repeated and excessive use of sunbeds and sunlamps or misuse of sunscreens which do not protect as efficiently for UVA than for UVB. Nevertheless, UVA radiation does induce skin carcinoma in mice, but has not yet exhibited the capacity to induce melanoma in animals that are responsive to UVB-induced melanoma. Meanwhile, UVA, as an oxidative stress inducer, is able to elicit a quite different photobiological response from UVB. The relative contribution of UVA to skin cancers in the human population is still unclear.

Abbreviations

UV	Ultraviolet
ROS	Reactive oxygen species
CPD	Cyclobutane pyrimidine dimer
(6–4)PP	Pyrimidine (6–4) pyrimidone photoproducts
8oxoG	8-Oxoguanine
SSB	Single strand break
DSB	Double strand break

Acknowledgements

Work of the authors is supported by Centre National de la Recherche Scientifique, Institut Curie and by a grant from the French “Agence Nationale pour la Recherche” (ANR-07-PCVI-0004-01).

References

1. J. C. Sutherland and K. P. Griffin, Absorption spectrum of DNA for wavelengths greater than 300 nm, Radiat. Res., 1981, 86, 399–409.
2. R. M. Tyrrell and M. Pidoux, Singlet oxygen involvement in the inactivation of cultured human fibroblasts by UVA (334 nm, 365 nm) and near-visible radiations, Photochem. Photobiol., 1989, 49, 407–412.
3. S. Basu-Modak and R. M. Tyrrell, Singlet oxygen. A primary effector in the UVA/near visible light induction of the human heme oxygenase gene, Cancer Res., 1993, 53, 4505–4510.
4. S. Ryter and R. M. Tyrrell, Singlet Molecular Oxygen (¹O₂): A Possible Effector of Eukaryotic Gene Expression, Free Radical Biol. Med., 1998, 24, 1520–1534.
5. F. El Ghissassi, R. Baan, K. Straif, Y. Grosse, B. Secretan, V. Bouvard, L. Benbrahim-Tallaa, N. Guha, C. Freeman, L. Galichet and V. Cogliano, WHO International Agency for Research on Cancer Monograph Working Group. A review of human carcinogens–part D: radiation, Lancet Oncol., 2009, 10, 751–752.
6. A. J. Ridley, J. R. Whiteside, T. J. McMillan and S. L. Allison, Cellular and sub-cellular responses to UVA in relation to carcinogenesis, Int. J. Radiat. Biol., 2009, 85, 177–195.
7. R. M. Tyrrell, Induction of pyrimidine dimers in bacterial DNA by 365 nm radiation, Photochem. Photobiol., 1973, 17, 69–73.
8. R. M. Tyrrell and R. B. Webb, Reduced dimer excision in bacteria following near-ultraviolet (365 nm) radiation, Mutat. Res., 1973, 19, 361–364.
9. R. M. Tyrrell, R. D. Ley and R. B. Webb, Induction of single-strand breaks (alkali-labile bonds) in bacterial and phage DNA by near UV (365 nm) radiation, Photochem. Photobiol., 1974, 20, 395–398.
10. M. J. Peak and J. G. Peak, Comparison of initial yields of DNA-to-protein cross-links and single-strand breaks induced in cultured human-cells by far- and near-ultraviolet light, bluelight and X-rays, Mutat. Res., 1991, 246, 187–191.
11. X. S. Zhang, B. S. Rosenstein, Y. Wang, M. Lebwohl, D. M. Mitchell and H. C. Wie, Induction of 8-oxo-7,8-dihydro-2′-deoxyguanosine by ultraviolet radiation in calf thymus DNA and HeLa cells, Photochem. Photobiol., 1997, 65, 119–124.
12. E. Kvam and R. M. Tyrrell, Induction of oxidative DNA base damage in human skin cells by UV and near visible radiation, Carcinogenesis, 1997, 18, 2379–2384.
13. T. Douki, D. Perdiz, P. Gróf, Z. Kuluncsics, E. Moustacchi, J. Cadet and E. Sage, Oxidation of guanine in cellular DNA by solar UV radiation: biological role, Photochem. Photobiol., 1999, 70, 184–190.
14. A. Besaratinia, T. W. Synold, H.-H. Chen, C. Chang, B. Xi, A. Riggs and G. P. Pfeifer, DNA lesions induced by UV A1 and B radiation in human cells: comparative analyses in the overall genome and in the p53 tumor suppressor gene, Proc. Natl. Acad. Sci. U. S. A., 2005, 102, 10058–10063.
15. A. Besaratinia, S. I. Kim and G. P. Pfeifer, Rapid repair of UVA-induced oxidized purines and persistence of UVB-induced dipyrimidine lesions determine the mutagenicity of sunlight in mouse cells, FASEB J., 2008, 22, 2379–2392.
16. A. Javeri, X. X. Huang, F. Bernerd, R. S. Mason and G. M. Halliday, Human 8-oxoguanine-DNA glycosylase 1 protein and gene are expressed more abundantly in the superficial than basal layer of human epidermis, DNA Repair, 2008, 7, 1542–1550.
17. C. Kielbassa, L. Roza and B. Epe, Wavelength dependence of oxidative DNA damage induced by UV and visible light, Carcinogenesis, 1997, 18, 811–816.
18. J.-P. Pouget, T. Douki, M.-J. Richard and J. Cadet, DNA damage induced in cells by gamma and UVA radiations as measured by HPLC/GC-MS, HPLC-EC and comet assay, Chem. Res. Toxicol., 2000, 13, 541–549.
19. T. Douki, A. Reynaud-Angelin, J. Cadet and E. Sage, Bipyrimidine photoproducts rather than oxidative lesions are the main type of DNA damage involved in the genotoxic effect of solar UVA radiation, Biochemistry, 2003, 42, 9221–9226.
20. J. Cadet, T. Douki, J. L. Ravanat and P. Di Mascio, Sensitized formation of oxidatively generated damage to cellular DNA by UVA radiation, Photochem. Photobiol. Sci., 2009, 8, 903–911.
21. C. A. Chadwick, C. S. Potten, O. Nikaido, T. Matsunaga, C. Proby and A. R. Young, The detection of cyclobutane thymine dimers,(6–4) photolesions and the Dewar valence photoisomers in sections of UV-irradiated human skin using specific antibodies, and the demonstration of depth penetration effects, J. Photochem. Photobiol., B, 1995, 28, 163–170.
22. R. Young, C. S. Potten, O. Nikaido, P. G. Parsons, J. Boenders, J. M. Ramsden and C. A. Chadwick, Human melanocytes and keratinocytes exposed to UVB or UVA in vivo show comparable levels of thymine dimers, J. Invest. Dermatol., 1998, 111, 936–940.
23. D. Perdiz, P. Gróf, M. Mezzina, O. Nikaido, E. Moustacchi and E. Sage, Distribution and repair of bipyrimidine photoproducts in solar UV-irradiated mammalian cells. Possible role of Dewar photoproducts in solar mutagenesis, J. Biol. Chem., 2000, 275, 26732–26742.
24. R. D. Ley and A. Fourtanier, UVAI-induced edema and pyrimidine dimers in murine skin, Photochem. Photobiol., 2000, 72, 485–487.
25. P. J. Rochette, J.-P. Therrien, R. Drouin, D. Perdiz, N. Bastien, E. A. Drobetsky and E. Sage, UVA-induced cyclobutane pyrimidine dimers form predominantly at thymine-thymine dipyrimidines and correlate with the mutation spectrum in rodent cells, Nucleic Acids Res., 2003, 31, 2786–2794.
26. S. Courdavault, C. Baudouin, M. Charveron, A. Favier, J. Cadet and T. Douki, Larger yield of cyclobutane dimers than 8 oxo-7,8-dihydroguanine in the DNA of UVA-irradiated human skin cells, Mutat. Res., 2004, 556, 135–142.
27. S. Mouret, C. Baudouin, M. Charveron, A. Favier, J. Cadet and T. Douki, Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed to UVA radiation, Proc. Natl. Acad. Sci. U. S. A., 2006, 103, 13765–13770.
28. J. Cadet, E. Sage and T. Douki, Ultraviolet radiation-mediated damage to cellular DNA, Mutat. Res., 2005, 571, 3–17.
29. A. P. Schuch, R. da Silva Galhardo, K. M. de Lima-Bessa, N. J. Schuch and C. F. Menck, Development of a DNA-dosimeter system for monitoring the effects of solar-ultraviolet radiation, Photochem. Photobiol. Sci., 2009, 8, 111–120.
30. P. H. Clingen, C. F. Arlett, L. Roza, T. Mori, O. Nikaido and M. H. Green, Induction of cyclobutane pyrimidine dimers, pyrimidine(6–4)pyrimidone photoproducts, and Dewar valence isomers by natural sunlight in normal human mononuclear cells, Cancer Res., 1995, 55, 2245–2248.
31. K. S. Wischermann, S. Popp, S. Moshir, K. Scharfetter-Kochanek, M. Wlaschek, F. de Gruijl, W. Hartschuh, R. Greinert, B. Volkmer, A. Faust, A. Rapp, P. Schmezer and P. Boukamp, UVA radiation causes DNA strand breaks, chromosomal aberrations and tumorigenic transformation in HaCaT skin keratinocytes, Oncogene, 2008, 27, 4269–4280.
32. P. M. Girard, M. Pozzebon, F. Delacôte, T. Douki, V. Smirnova and E. Sage, Inhibition of S-phase progression triggered by UVA-induced ROS does not require a functional DNA damage checkpoint response in mammalian cells, DNA Repair, 2008, 7(9), 1500–1516.
33. D. Dardalhon, A. Reynaud-Angelin, G. Baldacci, E. Sage and S. Francesconi, Unconventional effects of UVA radiation on cell cycle progression in S. pombe, Cell Cycle, 2008, 7(5), 611–622.
34. Z. Kuluncsics, D. Perdiz, E. Brulay, B. Muel and E. Sage, Wavelength dependence of ultraviolet-induced DNA damage distribution: involvement of direct or indirect mechanisms and possible artefacts, J. Photochem. Photobiol., B, 1999, 49, 71–80.
35. Y. Jiang, M. Rabbi, M. Kim, C. Ke, W. Lee, R. L. Clark, P. A. Mieczkowski and P. E. Marszalek, UVA generates pyrimidine dimers in DNA directly, Biophys. J., 2009, 96, 1151–1158.
36. S. Mouret, C. Philippe, J. Gracia-Chantegrel, A. Banyasz, S. Karpati, D. Markovitsi and T. Douki, UVA-induced cyclobutane pyrimidine dimers in DNA: a direct photochemical mechanism?, Org. Biomol. Chem., 2010, 8, 1706–1711.
37. P. M. Girard, S. Francesconi, D. Graindorge, P. J. Rochette, R. Drouin and E. Sage, UVA-induced Damage to DNA and proteins: direct versus indirect photochemical processes, J. Phys.: Conf. Ser., 2011, 261, 012002,  DOI:10.1088/1742-6596/261/1/012002.
38. A. Banyasz, I. Vayá, P. Changenet-Barret, T. Gustavsson, T. Douki and D. Markovitsi, Base pairing enhances fluorescence and favors cyclobutane dimer formation induced upon absorption of UVA radiation by DNA, J. Am. Chem. Soc., 2011, 133, 5163–5165.
39. D. E. Brash, J. A. Rudolph, J. A. Simon, A. Lin, G. J. McKenna, H. P. Baden, A. J. Halperin and J. Ponten, A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma, Proc. Natl. Acad. Sci. U. S. A., 1991, 88, 10124–10128.
40. G. P. Pfeifer, Y. H. You and A. Besaratinia, Mutations induced by ultraviolet light, Mutat. Res., 2005, 571, 19–31.
41. G. Giglia-Mari and A. Sarasin, TP53 mutations in human skin cancers, Hum. Mutat., 2003, 21, 217–228.
42. C. Greenman, P. Stephens, R. Smith, G. L. Dalgliesh, C. Hunter, G. Bignell, H. Davies, J. Teague, A. Butler, C. Stevens, S. Edkins, S. O'Meara, I. Vastrik, E. E. Schmidt, T. Avis, S. Barthorpe, G. Bhamra, G. Buck, B. Choudhury, J. Clements, J. Cole, E. Dicks, S. Forbes, K. Gray, K. Halliday, R. Harrison, K. Hills, J. Hinton, Jenkinson, D. Jones, A. Menzies, T. Mironenko, J. Perry, K. Raine, D. Richardson, R. Shepherd, A. Small, C. Tofts, J. Varian, T. Webb, S. West, S. Widaa, A. Yates, D. P. Cahill, D. N. Louis, P. Goldstraw, A. G. Nicholson, F. Brasseur, L. Looijenga, B. L. Weber, Y. E. Chiew, A. DeFazio, M. F. Greaves, A. R. Green, P. Campbell, E. Birney, D. F. Easton, G. Chenevix-Trench, M. H. Tan, S. K. Khoo, B. T. Teh, S. T. Yuen, S. Y. Leung, R. Wooster, P. A. Futreal and M. R. Stratton, Patterns of somatic mutation in human cancer genomes, Nature, 2007, 446, 153–158.
43. E. D. Pleasance, R. K. Cheetham, P. J. Stephens, D. J. McBride, S. J. Humphray, C. D. Greenman, I. Varela, M. L. Lin, G. R Ordonez, G. R. Bignell, K. Ye, J. Alipaz, M. J. Bauer, D. Beare, A. Butler, R. J. Carter, L. Chen, A. J. Cox, S. Edkins, P. I. Kokko-Gonzales, N. A. Gormley, R. J. Grocock, C. D. Haudenschild, M. M. Hims, T. James, M. Jia, Z. Kingsbury, C. Leroy, J. Marshall, A. Menzies, L. J. Mudie, Z. Ning, T. Royce, O. B. Schulz-Trieglaff, A. Spiridou, L. A. Stebbings, L. Szajkowski, J. Teague, D. Williamson, L. Chin, M. T. Ross, P. J. Campbell, D. R. Bentley, P. A. Futreal and M. R. Stratton, A comprehensive catalogue of somatic mutations from a human cancer genome, Nature, 2009, 463, 191–196.
44. T. M. Rünger and U. P. Kappes, Mechanisms of mutation formation with long-wave ultraviolet light (UVA), Photodermatol., Photoimmunol. Photomed., 2008, 24, 2–10.
45. E. A. Drobetsky, J. Turcotte and A. Chateauneuf, A role for ultraviolet A in solar mutagenesis, Proc. Natl. Acad. Sci. U. S. A., 1995, 92, 2350–2354.
46. T. Negishi, C. Nagaoka, H. Hayatsu, K. Suzuki, T. Hara, M. Kubota, M. Watanabe and K. Hieda, Somatic-cell mutation induced by UVA and monochromatic UV radiation in repair-proficient and -deficient Drosophila melanogaster, Photochem. Photobiol., 2001, 73, 493–498.
47. S. Kozmin, G. Slezak, A. Reynaud-Angelin, C. Elie, Y. de Ryck, S. Boiteux and E. Sage, Ultraviolet A radiation is highly mutagenic in cells that are unable to repair 7,8-dihydro-8-oxoguanine in Saccharomyces cerevisiae, Proc. Natl. Acad. Sci. U. S. A., 2005, 102, 13538–13543.
48. S. I. Kim, G. P. Pfeifer and A. Besaratinia, Mutagenicity of ultraviolet A radiation in the lacI transgene in Big Blue mouse embryonic fibroblasts, Mutat. Res., 2007, 617, 71–78.
49. E. Sage, B. Lamolet, E. Brulay, E. Moustacchi, A. Chateauneuf and E. A. Drobetsky, Mutagenic specificity of solar UV light in nucleotide excision repair-deficient rodent cells, Proc. Natl. Acad. Sci. U. S. A., 1996, 93, 176–180.
50. C. Robert, B. Muel, A. Benoit, L. Dubertret, A. Sarasin and A. Stary, Cell survival and shuttle vector mutagenesis induced by ultraviolet A and ultraviolet B radiation in a human cell line, J. Invest. Dermatol., 1996, 106, 721–728.
51. U. P. Kappes, D. Luo, M. Potter, K. Schulmeister and T. M. Rünger, Short- and long-wave UV light (UVB and UVA) induce similar mutations in human skin cells, J. Invest. Dermatol., 2006, 126, 667–675.
52. S. Shibutani, M. Takeshita and A. P. Grollman, Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG, Nature, 1991, 349, 431–434.
53. U. P. Kappes and T. M. Rünger, No major role for 7,8-dihydro-8-oxoguanine in ultraviolet light-induced mutagenesis, Radiat. Res., 2005, 164, 440–445.
54. A. Besaratinia, T. W. Synold, B. Xi and G. P. Pfeifer, G-to-T transversions and small tandem base deletions are the hallmark of mutations induced by ultraviolet A radiation in mammalian cells, Biochemistry, 2004, 43, 8169–8177.
55. A. Besaratinia, S. I. Kim, S. E. Bates and G. P. Pfeifer, Riboflavin activated by ultraviolet A1 irradiation induces oxidative DNA damage-mediated mutations inhibited by vitamin C, Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 5953–5958.
56. S. G. Kozmin, Y. I. Pavlov, T. A. Kunkel and E. Sage, Roles of Saccharomyces cerevisiae DNA Polymerases Polη and Polζ in Response to Irradiation by Simulated Sunlight, Nucleic Acids Res., 2003, 31, 4541–4552.
57. A. Biverstål, R. Johansson, D. Jenssen and K. Erixon, Cyclobutane pyrimidine dimers do not fully explain the mutagenicity induced by UVA in Chinese hamster cells, Mutat. Res., 2008, 648, 32–39.
58. J. van Kranen, A. de Laat, J. van de Ven, P. W. Wester, A. de Vries, R. J. Berg, C. F. van Kreijl and F. R. de Gruijl, Low incidence of p53 mutations in UVA (365-nm)-induced skin tumors in hairless mice, Cancer Res., 1997, 57, 1238–1240.
59. H. Ikehata, K. Kawai, J. Komura, K. Sakatsume, L. Wang, M. Imai, S. Higashi, O. Nikaido, K. Yamamoto, K. Hieda, M. Watanabe, H. Kasai and T. Ono, UVA1 genotoxicity is mediated not by oxidative damage but by cyclobutane pyrimidine dimers in normal mouse skin, J. Invest. Dermatol., 2008, 128, 2289–2296.
60. H. Ikehata, S. Nakamura, T. Asamura and T. Ono, Mutation spectrum in sunlight-exposed mouse skin epidermis: small but appreciable contribution of oxidative stress-mediated mutagenesis, Mutat. Res., 2004, 556, 11–24.
61. E. Persson, D. W. Edström, H. Bäckvall, J. Lundeberg, F. Pontén, A. M. Ros and C. Williams, The mutagenic effect of ultraviolet-A1 on human skin demonstrated by sequencing the p53 gene in single keratinocytes, Photodermatol., Photoimmunol. Photomed., 2002, 18, 287–293.
62. X. X. Huang, F. Bernerd and G. M. Halliday, Ultraviolet A within sunlight induces mutations in the epidermal basal layer of engineered human skin, Am. J. Pathol., 2009, 174, 1534–1543.
63. N. S. Agar, G. M. Halliday, R. S. Barnetson, H. N. Ananthaswamy, M. Wheeler and A. M. Jones, The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: a role for UVA in human skin carcinogenesis, Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 4954–4959.
64. E. C. Friedberg, G. C. Walker and W. Siede, DNA repair and mutagenesis, 1995, ASM Press, Washington, DC.
65. A. A. Schothorst, L. M. Evers, K. C. Noz, R. Filon and A. A. van Zeeland, Pyrimidine dimer induction and repair in cultured human skin keratinocytes or melanocytes after irradiation with monochromatic ultraviolet radiation, J. Invest. Dermatol., 1991, 96, 916–920.
66. S. Gaddameedhi, M. G. Kemp, J. T. Reardon, J. M. Shields, S. L. Smith-Roe, W. K. Kaufmann and A. Sancar, Similar nucleotide excision repair capacity in melanocytes and melanoma cells, Cancer Res., 2010, 70, 4922–4930.
67. H. T. Wang, B. Choi and M. S. Tang, Melanocytes are deficient in repair of oxidative DNA damage and UV-induced photoproducts, Proc. Natl. Acad. Sci. U. S. A., 2010, 107(27), 12180–12185.
68. J. Dahle and E. Kvam, Induction of delayed mutations and chromosomal instability in fibroblasts after UVA-, UVB-, and X-radiation, Cancer Res., 2003, 63, 1464–1469.
69. J. Dahle, P. Noordhuis, T. Stokke, D. H. Svendsrud and E. Kvam, Multiplex polymerase chain reaction analysis of UV-A- and UV-B-induced delayed and early mutations in V79 Chinese hamster cells, Photochem. Photobiol., 2005, 81, 114–119.
70. R. P. Phillipson, S. E. Tobi, J. A. Morris and T. J. McMillan, UV-A induces persistent genomic instability in human keratinocytes through an oxidative stress mechanism, Free Radical Biol. Med., 2002, 32, 474–480.
71. S. Oikawa, S. Tada-Oikawa and S. Kawanishi, Site-specific DNA damage at the GGG sequence by UVA involves acceleration of telomer shortening, Biochemistry, 2001, 40, 4763–4768.
72. M. Buckingham and A. J. Klingelhutz, The role of telomeres in the ageing of human skin, Exp. Dermatol., 2011, 20(4), 297–302.
73. J. Ye, Y. Wu and E. Gilson, Dynamics of telomeric chromatin at the crossroads of aging and cancer, Essays Biochem., 2010, 48(1), 147–164.
74. P. J. Rochette and D. E. Brash, Human telomeres are hypersensitive to UV-induced DNA damage and refractory to repair, PLoS Genet., 2010, 6(4), e1000926.
75. P. Grof, G. Ronto and E. Sage, A computational study of physical and biological characterization of common UV sources and filters, and their relevance for substituting sunlight, J. Photochem. Photobiol., B, 2002, 68, 53–59.
76. G. M. Halliday, N. S. Agar, R. S. Barnetson, H. N. Ananthaswamy and A. M. Jones, UV-A fingerprint mutations in human skin cancer, Photochem. Photobiol., 2005, 81, 3–8.
77. A. de Laat, J. C. van der Leun and F. R. de Gruijl, Carcinogenesis induced by UVA (365-nm) radiation: the dose-time dependence of tumor formation in hairless mice, Carcinogenesis, 1997, 18, 1013–1020.
78. S. Q. Wang, R. B. Setlow, M. Berwick, D. Polsky, A. A. Marghooh, A. W. Kopf and R. S. Bart, Ultraviolet A and melanoma: a review, J. Am. Acad. Dermatol., 2001, 44, 837–846.
79. C. Jhappan, F. P. Noonan and G. Merlino, Ultraviolet radiation and cutaneous malignant melanoma, Oncogene, 2003, 22, 3099–3112.
80. D. C. Bennett, Ultraviolet wavebands and melanoma initiation, Pigm. Cell Melanoma Res., 2008, 21, 520–524.
81. R. B. Setlow, E. Grist, K. Thompson and A. D. Woodhead, Wavelengths effective in induction of malignant melanoma, Proc. Natl. Acad. Sci. U. S. A., 1993, 90, 6666–6670.
82. L. Mitchell, A. A. Fernandez, R. S. Nairn, R. Garcia, L. Paniker, D. Trono, H. D. Thames and I. Gimenez-Conti, Ultraviolet A does not induce melanomas in a Xiphophorus hybrid sh model, Proc. Natl. Acad. Sci. U. S. A., 2010, 107(20), 9329–9334.
83. R. D. Ley, Ultraviolet radiation A-induced precursors of cutaneous melanoma in Monodelphis domestica, Cancer Res., 1997, 57(17), 3682–3684.
84. C. De Fabo, F. P. Noonan, T. Fears and G. Merlino, Ultraviolet B but not ultraviolet Aradiation initiates melanoma, Cancer Res., 2004, 64, 6372–6376.
85. P. Autier, J.-F. Doré, A. M. M. Eggermont and J. W. Coebergh, Epidemiological evidence that UVA radiation is involved in the genesis of cutaneous melanoma, Curr. Opin. Oncol., 2011, 23, 189–196.
86. M. R. Chedekel, S. K. Smith, P. W. Post, A. Pokora and D. L. Vessell, Photodestruction of pheomelanin: role of oxygen, Proc. Natl. Acad. Sci. U. S. A., 1978, 75, 5395–5399.
87. N. Kollias, R. M. Sayre, L. Zeise and M. R. Chedekel, Photoprotection by melanin, J. Photochem. Photobiol., B, 1991, 9, 135–160.
88. S. Takeuchi, W. Zhang, K. Wakamatsu, S. Ito, V. Hearing, K. H. Kraemer and D. E. Brash, Melanin acts as a potent UVB photosensitizer to cause an atypical mode of cell death in murine skin, Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 15076–15081.
89. E. Kvam and R. M. Tyrrell, The role of melanin in the induction of oxidative DNA base damage by ultraviolet A irradiation of DNA or melanoma cells, J. Invest. Dermatol., 1999, 113(2), 209–203.
90. M. Berneburg and J. Krutmann, Photoageing-associated large-scale deletions of mitochondrial DNA, Methods Enzymol., 2000, 319(34), 366–376.
91. M. A. Birch-Machin and H. Swalwell, How mitochondria record the effects of UVexposure and oxidative stress using human skin as a model tissue, Mutagenesis, 2009, 25(2), 101–107.
92. M. Berneburg, S. Grether-Beck, V. Kürten, T. Ruzicka, K. Briviba, H. Sies and J. Krutmann, Singlet oxygen mediates the UVA-induced generation of the photoaging-associated mitochondrial common deletion, J. Biol. Chem., 1999, 274(22), 15345–1549.
93. M. Berneburg, T. Gremmel, V. Kürten, P. Schroeder, I. Hertel, A. von Mikecz, S. Wild, M. Chen, L. Declercq, M. Matsui, T. Ruzicka and J. Krutmann, Creatine supplementation normalizes mutagenesis of mitochondrial DNA as well as functional consequences, J. Invest. Dermatol., 2005, 125(2), 213–220.
94. D. Mitchell and A. Fernandez, The photobiology of melanocytes modulates the impact of UVA on sunlight-induced melanoma, Photochem. Photobiol. Sci., 2011, 10 10.1039/c1pp05146f.
95. J.-F. Doré and M.-C. Chignol, Tanning salons and skin cancer, Photochem. Photobiol. Sci., 2011, 10 10.1039/c1pp05186e.

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Footnote

† Contribution to the themed issue on the biology of UVA.

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