SEARCH

SEARCH BY CITATION

Keywords:

  • mutagenesis;
  • ultraviolet light;
  • UVA;
  • UV-induced DNA damage

Summary

  1. Top of page
  2. Summary
  3. Formation of DNA damage and mutations following exposure to different wavelengths of UV light
  4. UVA also generates pyrimidine dimers
  5. Mutations induced by UVA in cultured cells
  6. Mutations in UVA-irradiated skin
  7. Mutations in UVA-induced tumours
  8. Are UVA-induced pyrimidine dimers more mutagenic than UVB-induced pyrimidine dimers?
  9. Clinical Relevance
  10. References

Long-wave ultraviolet (UV) A light is able to damage DNA, to cause mutations, and to induce skin cancer, but the exact mechanisms of UVA-induced mutation formation remain a matter of debate. While pyrimidine dimers are well established to mediate mutation formation with shortwave UVB, other types of DNA damage, such as oxidative base damage, have long been thought to be the premutagenic lesions for UVA mutagenesis. However, pyrimidine dimers can also be generated by UVA, and there are several lines of evidence that these are the most important premutagenic lesions not only for UVB- but also for UVA-induced mutation formation. C[RIGHTWARDS ARROW]T transition mutations, which are generated by pyrimidine dimers, are called UV-signature mutations. They cannot be interpreted to be solely UVB-induced, as they are induced by UVA as well. Furthermore, there is no consistent evidence for a separate UVA-signature mutation that is only generated with UVA. We hypothesize that a weaker anti-mutagenic cellular response, but not a different type of DNA damage, may be responsible for a higher mutation rate per DNA photoproduct with UVA, as compared with UVB.

It is well established that exposure of the skin to solar ultraviolet (UV) light is a major risk factor for the development of malignant melanoma and non-melanoma skin cancer, and that this effect is mediated by a chain of events, which includes the formation of DNA damage by UV light and subsequent formation of mutations (1). Most of the mutagenic and carcinogenic properties of sunlight have long been attributed to the short-wavelength range (UVB; 280–315 nm) of the solar UV spectrum. Despite being well-known that long-wavelength UV light (UVA; 315–400 nm) can also damage DNA and that it has mutagenic and carcinogenic properties (2), the relevance of UVA effects for solar mutagenesis and skin carcinogenesis and the mechanisms by which it induces mutations remain matters of debate.

There are several lines of evidence suggesting that UVA might play a particularly important role in the pathogenesis of cutaneous malignant melanoma (3–5):

  • 1
    Meta-analyses of multiple retrospective studies and one large prospective study indicate that the use of tanning beds (which contain mostly high-dose UVA emitters) increases the risk for melanoma (6, 7).
  • 2
    Melanomas have been described in unusual locations on the skin of tanning bed users (8).
  • 3
    In melanoma-prone xiphophorus fish, both UVA and UVB induce melanomas. When considering the much higher abundance of UVA in natural sunlight, it was calculated that 90–95% of sun-induced melanomas may be attributed to longer wavelengths (>320 nm) (9).
  • 4
    UVA but not UVB induces melanoma precursors in the opossum. However, UVA-induced melanoma precursors did not progress to invasive melanomas (10).
  • 5
    Use of sunscreens (which for a long time did not filter UVA at all or only very poorly, and even today provide less protection against UVA than against UVB) may increase melanoma risk (11). Individuals commonly use sunscreens to prolong the time they can spend in the sun without sunburning. This actually increases exposure to the less filtered or unfiltered UVA.

More recently, however, the putative link between UVA exposure and melanoma has been questioned, as only UVB, but not UVA induced melanoma in a transgenic mouse model (12).

More than 90% of the UV emission of natural sunlight reaching the earth's surface is UVA. Other sources of UVA are high-fluence UVA emitters used in commercial tanning devices and for medical phototherapy. In order to establish risk assessments and good photo-protection strategies, it is therefore of utmost importance to understand the carcinogenic properties of UVA. One importance piece of information in this endeavor is to understand how UVA induces mutations.

Formation of DNA damage and mutations following exposure to different wavelengths of UV light

  1. Top of page
  2. Summary
  3. Formation of DNA damage and mutations following exposure to different wavelengths of UV light
  4. UVA also generates pyrimidine dimers
  5. Mutations induced by UVA in cultured cells
  6. Mutations in UVA-irradiated skin
  7. Mutations in UVA-induced tumours
  8. Are UVA-induced pyrimidine dimers more mutagenic than UVB-induced pyrimidine dimers?
  9. Clinical Relevance
  10. References

Different wavelengths of UV light induce different types of DNA damage. Through direct excitation of the DNA molecule, UVB generates DNA photoproducts, mostly cyclobutane pyrimidine dimers (CPDs) and pyrimidine (4–6) pyrimidone photoproducts (6,4-PPs). These photoproducts generate typical mutations, namely C[RIGHTWARDS ARROW]T transitions, by misincorporation of adenine opposite cytosine during replication. Such mutations are commonly found in UV-induced skin cancers, but only rarely in internal malignancies. These transitions, including the CC[RIGHTWARDS ARROW]TT tandem mutations, have been termed ‘UV-signature mutations (13, 14). They are in fact signature mutations for pyrimidine dimers, and it is generally accepted that pyrimidine dimers are the major premutagenic lesions for UVB. Both the CPD and the 6,4-PP are observed at all possible di-pyrimidine sites, with the thymine–thymine dimer being the most common CPD and the thymine–cytosine dimer being the most common 6,4-PP. Upon further irradiation with UV wavelengths between 280 and 360 nm, the normal isomers of 6,4-PP can be converted to their Dewar valence isomers, which are probably less mutagenic than the normal isomers but may still contribute to solar mutagenesis (15). A few other rare DNA photoproducts have been described, such as complex purine lesions and pyrimidine hydrates, but their physiological significance in the photobiology of human skin is unknown.

The absorption maximum of DNA is at 260 nm. This makes UVC the most effective wavelength for the induction of DNA photoproducts in naked DNA. However, in vivo, due to the absorption of shorter wavelengths in the upper layers of the epidermis, 300 nm, which is within the UVB range, is the most effective wavelength for inducing DNA photoproducts in the basal layer of the epidermis (Fig. 1).

image

Figure 1.  Action spectra of DNA damage and skin cancer formation. Redrawn after data from (17, 34, 36, 70); CPD, cyclopyrimidine dimers.

Download figure to PowerPoint

The types of UV-induced DNA damage discussed thus far result from the direct absorption of photons by DNA bases. However, UV radiation can also damage DNA indirectly (16). After absorption of photons by chromophores other than DNA, energy can be transferred either to DNA (type I photosensitized reaction), or to molecular oxygen, with reactive oxygen species in turn damaging the DNA molecule (type II photosensitized reaction). The indirect generation of oxidative DNA damage has been suggested to underlie UVA mutagenesis and carcinogenesis. However, formation of oxidative DNA damage is not limited to UVA, as it can also be formed by UVB (Fig. 1) and even visible light (17).

UV-induced reactive oxygen species include singlet oxygen and probably other non-radical and radical reactive oxygen species, such as hydrogen peroxide and the superoxide radical (18). Even the highly reactive hydroxyl radical may be formed by a reaction of hydrogen peroxide with nuclear metals through a Fenton reaction. This oxidative stress not only affects DNA but also membranes and proteins, and the relative contribution of each (oxidative membrane damage, oxidative protein damage, oxidative DNA damage) to the different biologic effects of UV irradiation has not been well established.

Singlet oxygen and the other reactive oxygen species react predominantly with guanine and generate several DNA changes including the mutagenic and well-studied 7,8-dihydro-8-oxyguanine (8-oxoG). This lesion is known to cause G[RIGHTWARDS ARROW]T transversions through mispairing of 8-oxoG with adenine, or A[RIGHTWARDS ARROW]C transversions through misincorporation of 8-oxoG nucleotides opposite adenine (19, 20). As 8-oxoG is more readily generated by wavelengths above 350 nm (17) (Fig. 1), oxidative DNA damage has been suggested to contribute to mutagenesis and carcinogenesis particularly with the longer wavelength of UVA (18).

While the guanine base is most commonly affected by oxidative assaults, reactive oxygen species can damage other DNA bases as well (21). For example thymine glycol is an oxidative thymine lesion that has been reported to be induced by UV (22), and may give rise to T[RIGHTWARDS ARROW]C transitions (23). The oxygen radicals, but not singlet oxygen, are also capable of introducing DNA strand breaks. These may give rise to deletions, insertions, and other more complex mutations. These oxygen radical-induced DNA strand breaks are different from those generated as repair intermediates, e.g. through incision by nucleotide excision repair at sites of a pyrimidine dimer or through incision by base excision repair at oxidative DNA lesions. And indeed, the vast majority of DNA strand breaks observed after UVA or UVB were actually shown to represent repair intermediates, and not directly UV- or reactive oxygen species-induced breaks (24). Single-strand breaks, should they be directly UV induced, are commonly thought to be repaired rapidly and efficiently. They are probably innocuous lesions and may have little involvement in the formation of deletions or insertions. This is different for DNA double-strand breaks. However, there is good evidence that these are not formed efficiently by UV light (25).

UVA also generates pyrimidine dimers

  1. Top of page
  2. Summary
  3. Formation of DNA damage and mutations following exposure to different wavelengths of UV light
  4. UVA also generates pyrimidine dimers
  5. Mutations induced by UVA in cultured cells
  6. Mutations in UVA-irradiated skin
  7. Mutations in UVA-induced tumours
  8. Are UVA-induced pyrimidine dimers more mutagenic than UVB-induced pyrimidine dimers?
  9. Clinical Relevance
  10. References

The ability of UVA to generate photoproducts (CPDs and 6,4-PPs) has long been denied. In recent years, however, UVA has been shown to generate at least some photoproducts, in vitro (=in naked DNA and in cultured cells) and in vivo (=in irradiated skin) (17, 21, 26–31). This raises the question of whether the mutagenic properties of UVA (in particular UVA1: 340–400 nm) are really mediated by oxidative DNA damage or by the weak ability of UVA to form a few pyrimidine dimers. It has been suggested that UVA may generate CPDs via a photosensitized triplet energy transfer in contrast to formation via direct excitation of DNA by UVB (32, 33). In any case, UVA generates much fewer DNA photoproducts than UVB, e.g. by a factor of approximately 10 000–100 000, when comparing 300 with 360 nm (Fig. 1). Even when considering that natural sunlight contains 10–1 000-fold more UVA than UVB (depending on several variables, including the time of the day and cloud cover), the contribution of UVA to sunlight-induced DNA photoproducts has to be considered small, accounting for only 0.01–10% of photoproducts generated by exposure to natural sunlight. When making such calculations, however, it is important to keep in mind that the separation between UVB and UVA is arbitrary, and that both are part of a spectrum of wavelengths with gradually changing photo-physical, photo-chemical, and photo-biological properties.

When superimposing the action spectra for formation of CPDs and for skin cancer formation in mice (34) (Fig. 1), it becomes apparent that both curves run parallel in the UVB range and in the shorter-wavelength range of UVA, up to approximately 350 nm. This has been interpreted as evidence that DNA photoproducts mediate skin carcinogenesis with UVB and UVA2 (315–340 nm). With longer wavelengths, in particular above 350 nm, the efficacy of CPD formation further declines, whereas the skin cancer action spectrum exhibits a second peak (Fig. 1). This has been interpreted such that a different type of DNA lesion significantly contributes to skin cancer formation with wavelengths above 350 nm (34, 35).

This interpretation was further supported by Enninga et al. (36). They examined mutation frequencies and photoproduct formation after exposure to different wavelengths of UVB or UVA, and found that mutation formation per DNA photoproduct increased with increasing wavelength from the UVB to the UVA range.

Mutations induced by UVA in cultured cells

  1. Top of page
  2. Summary
  3. Formation of DNA damage and mutations following exposure to different wavelengths of UV light
  4. UVA also generates pyrimidine dimers
  5. Mutations induced by UVA in cultured cells
  6. Mutations in UVA-irradiated skin
  7. Mutations in UVA-induced tumours
  8. Are UVA-induced pyrimidine dimers more mutagenic than UVB-induced pyrimidine dimers?
  9. Clinical Relevance
  10. References

The hypothesis that UVA-induced mutations, in particular those induced by UVA1 (340–400 nm), are caused by oxidative DNA damage or DNA lesions other than pyrimidine dimers can be tested by reviewing what types of mutations have been reported to be caused by UVA. If UVA-induced mutations were caused by 8-oxoG, a high ratio of G[RIGHTWARDS ARROW]T and A[RIGHTWARDS ARROW]C transversions would be expected. Accordingly, if UVA-induced mutations were caused by pyrimidine dimers, a high ratio of C[RIGHTWARDS ARROW]T transitions should be found in the spectrum of UVA-induced mutations. It is important to keep in mind, however, that it is not possible to conclude with absolute certainty which type of DNA damage (=premutagenic lesion) initiated a particular mutation, because many types of base substitution mutations have been shown to be generated by different types of DNA damage. Even CC[RIGHTWARDS ARROW]TT tandem mutations, commonly regarded as highly specific for pyrimidine dimers, have also been reported after the formation of oxidative DNA damage (37). Because most mutations are thought to be introduced during replication of damaged templates, and because pyrimidine dimers always form between adjacent pyrimidines, many researchers feel certain to assign a strand location of a premutagenic DNA lesion. This might be true for UVC, which almost exclusively generates pyrimidine dimers, but not for UVB and UVA, where various different kinds of DNA damage are formed. The ambiguity of strand assignment of the premutagenic lesion is further supported by the example of singlet oxygen-induced DNA damage, which can, as mentioned above, either damage the template (guanine in the DNA strand) or the substrate (guanine nucleotide) (31).

The first comprehensive work on mutations induced by different wavelengths of UV light, including UVA, was published by Drobetsky et al. (38) in 1995. They found a much lower frequency of C[RIGHTWARDS ARROW]T transitions with UVA, as compared with UVB or solar-simulated light (SSL) (Table 1), suggesting that pyrimidine dimers may indeed play a lesser role in UVA mutagenesis. In contrast to UVB or UVC, they found a high ratio of T[RIGHTWARDS ARROW]G (=A : T[RIGHTWARDS ARROW]C : G) transversions with UVA and suggested this to be a fingerprint mutation for UVA mutagenesis. A high ratio of such mutations in the spectrum of SSL-induced mutations was considered to be an indication that UVA contributes significantly to mutation formation by natural sunlight. As discussed above, T[RIGHTWARDS ARROW]G transversions may be formed by incorporation of 8-oxoG nucleotides opposite of adenine. However, G[RIGHTWARDS ARROW]T transversions, the other type of mutation commonly caused by 8-oxoG, were not commonly observed, and it is hard to imagine that UVA damages only guanine in the nucleotide pool, but not in the DNA pool. Therefore, a significant contribution of 8-oxoG to UVA-mutagenesis appears unlikely. The authors discussed that the identity of the premutagenic photoproduct responsible for T[RIGHTWARDS ARROW]G mutations remained to be established and suggested either pyrimidine dimers or an unidentified DNA photoproduct to cause this type of mutation. A role of pyrimidine dimers was further supported by the observation of some UVA-induced CC[RIGHTWARDS ARROW]TT tandem mutations and the location of most UVA-induced mutations in di-pyrimidine locations. While this report was a very important piece of information to further the understanding of how different wavelengths contribute to UV mutagenesis, several limitations caution the application of these data to the human situation: (1) Chinese hamster ovary (CHO) cells were used. Like all rodent cells, these have very different DNA repair capabilities from human cells (rodent repairadox; (39)); (2) transformed cells, like the established CHO cell lines used, most commonly have fundamentally altered cellular DNA damage responses, e.g. through inactivation of p53 (40, 41), and these are likely to affect the frequency and the types of mutations formed; (3) as the spontaneous mutation frequency with these CHO cells was high, irradiation with high doses of UVA for 2 h was needed, and the observed frequency of UVA-induced mutations was still only three to five fold above the background of the spontaneous mutation frequency. This means that 20–33% of the mutations observed after UVA irradiation were actually not induced by UVA, but represent spontaneous mutation events.

Table 1.   Published spectra of UVA-induced mutations in cultured cells
PublicationDrobetsky et al. (38)Robert et al. (42)Besaratinia et al. (43)Kappes et al. (44)
Model systemTransformed hamster cells (CHO)Transformed human embryonic kidney cellsTransgenic Big Blue mouse embryonal fibroblastsPrimary human neonatal skin fibroblasts
Mutation assayaprt-assaylacZ on stably transfected plasmidLambda shuttle, cll mutagenesis targethprt-assay
UVCUVBUVASSLUVB*UVA*UVAUVBUVA
  • *

    In parentheses, numbers of point mutations only.

  • Number of confirmed mutations, excluding ‘jackpot mutations’.

  • SSL, solar simulated light; CHO, Chinese hamster ovary.

Number of mutants sequenced5974543646 (34)36 (22)1395246
Presumably induced by pyrimidine dimmers
 C[RIGHTWARDS ARROW]T (including CC[RIGHTWARDS ARROW]TT)62%71%27%36%50% (68%)33% (54%)305648
Presumably induced by 8-oxoG
 G[RIGHTWARDS ARROW]T0%1%4%0%3% (4%)3% (5%)251311
 A[RIGHTWARDS ARROW]C5%9%37%25%2% (3%)0% (0%)1120
Possibly induced by thymine glycol
 T[RIGHTWARDS ARROW]C7%0%9%3%4% (6%)14% (23%)111713
Possibly induced by strand breaks
 Insertions, deletions, frameshifts, duplications2%4%2%0%26%36%10011

Another report that compares UVA- and UVB-induced mutations was published by Robert et al. (42), who used adenovirus-transformed human embryonic kidney cells stably transfected with a plasmid carrying the lacZ bacterial gene as a mutagenesis target (Table 1). They did not find any T[RIGHTWARDS ARROW]G mutations (those suggested to be UVA-fingerprint mutations by Drobetsky et al. (38)) with UVA (or with UVB) (Table 1). Shuttle vectors are prone to deletion or insertion mutations and these were indeed found at a much higher frequency than in the work by Drobetsky et al., both with UVB and with UVA. It is most likely that these represent differences in DNA processing between episomal plasmid DNA and genomic DNA and cannot be considered to be typical UV-induced mutations. However, there were more of such mutations observed after UVA than after UVB exposure (36% vs. 26%). This 10% difference may indicate that UVA-induced strand breaks, caused, e.g. by oxygen radicals, may have generated some of these mutations. However, this difference is based on a small number of mutants (12 non-point mutations/46 total mutations with UVB vs. 13/36 with UVA). When calculating fractions of mutation types based only on the observed single base exchange mutations (shown in brackets in Table 1), the C[RIGHTWARDS ARROW]T transitions (typical for pyrimidine dimers) were the most common mutations observed with UVB (68%) and with UVA (54%). This suggests that pyrimidine dimers were the predominant premutagenic lesions not only with UVB but also with UVA. In addition, there were very few G[RIGHTWARDS ARROW]T transversions, confirming that it is very unlikely that 8-oxoG is a major player in UVA-mutagenesis. While this study used human cells, an advantage over the study by Drobetsky et al. (38), it still used transformed cells and not skin cells. Furthermore, the episomal mutagenesis target might further limit the interpretability of the observed phenomena to reflect mutation formation in genomic DNA of human skin.

A third study that reports a spectrum of UVA-induced mutations in cultured cells was published by Besaratinia et al. (43), who used Big Blue mouse embryonal fibroblasts with a recoverable λ vector carrying the cll gene as a mutagenesis target. They compared the spectrum of UVA-induced mutations with a spectrum of spontaneous mutations, but not with a spectrum of UVB-induced mutations (Table 1). In contrast to Drobetsky et al. (38) and Robert et al. (42), they found a significant fraction (25%) of UVA-induced mutations to be G[RIGHTWARDS ARROW]T transversions, pointing to a significant contribution of 8-oxoG to UVA mutagenesis. However, the most common type of mutation was the C[RIGHTWARDS ARROW]T transition (30%), the signature mutation for pyrimidine dimers. The authors comment that this does not point to pyrimidine dimers as premutagenic lesions, because the fraction of C[RIGHTWARDS ARROW]T in the untreated controls was even higher (35%). However, because the UVA-induced mutation frequency was about fivefold higher than the spontaneous mutation frequency, the majority of C[RIGHTWARDS ARROW]T transitions have to be considered UVA induced and therefore, in our opinion, do point to pyrimidine dimers as the underlying premutagenic lesion. Similar to the work by Drobetsky et al. (38), these investigations were conducted using rodent cells (see the discussion above on the limits of rodent cells as model systems).

We recently published work that describes spectra of mutations induced by UVA and by UVB in the hprt gene of cultured primary (=non-transformed) human skin fibroblasts (44). Increasing mutation frequencies were observed with increasing doses of UVA or UVB. With 200 kJ/m2 UVA, the induced mutation frequency was 235-fold, and with 200 J/m2 UVB 68-fold higher than the spontaneous mutation frequency. These numbers indicate that the vast majority of mutations observed in UV-irradiated skin samples were indeed induced by UV, and do not represent spontaneous mutation events. In these dose ranges, cells exhibited a similar, mild to moderate cytotoxicity. Comparing roughly equitoxic doses (200 kJ/m2 UVA vs. 200 J/m2 UVB), our UVA source generated 3.5-fold more mutations than UVB. This means that UVB yields approximately 300-fold more mutations per J/m2 than UVA (as we are comparing a 1000-fold lower dose of UVB with the UVA dose).

Sequencing of recovered mutants revealed (Table 1), as expected, that the majority of UVB-induced mutations were C[RIGHTWARDS ARROW]T transitions, confirming the contribution of pyrimidine dimers to UVB mutagenesis. To our surprise, the majority of UVA-induced mutations had all the features of being induced by pyrimidine dimers as well. These were as follows:

  • 1
    As with UVB, the majority of UVA-induced mutations were also C[RIGHTWARDS ARROW]T transitions;
  • 2
    As with UVB, most of the UVA-induced C[RIGHTWARDS ARROW]T transitions were also located within runs of pyrimidines;
  • 3
    CC[RIGHTWARDS ARROW]TT tandem mutations occurred with both UVA and UVB;
  • 4
    UVA- and UVB-induced C[RIGHTWARDS ARROW]T transitions shared most of the six hotspots for C[RIGHTWARDS ARROW]T transition formation;
  • 5
    Both UVA- and UVB-induced C[RIGHTWARDS ARROW]T transitions exhibited a predominant location on the non-transcribed strand (85% and 78% with UVA and UVB, respectively), an expected result for mutations formed by photoproducts, as these are more rapidly removed from the transcribed strand (45). This largely excludes the possibility that the premutagenic lesion that induced C[RIGHTWARDS ARROW]T transitions with UVA (or with UVB) involved the guanine base opposite of cytosine.
  • 6
    The spectrum of mutation types was very similar for UVA and UVB.

Types of mutations that might have been induced by oxidative DNA damage (G[RIGHTWARDS ARROW]T, A[RIGHTWARDS ARROW]C, T[RIGHTWARDS ARROW]C mutations) were much less common than C[RIGHTWARDS ARROW]T mutations and were about as common with UVA as with UVB. This indicates that oxidative DNA damage does not play a predominant role in UVA mutagenesis.

Insertions and deletions occurred at a rate of 11% in UVA-induced mutations, but were not observed with UVB. This may indicate, similar to the work by Robert et al. (42), that DNA breaks, generated, e.g. through UVA-induced oxygen radicals, may contribute to some, albeit not a majority of UVA-induced mutations.

Further indication that oxidative DNA damage, in particular 8-oxoG, is not a major contributor to UVA mutagenesis comes from our work, in which we compared the frequencies of UVA- (and UVB-) induced mutations in fibroblasts from OGG1 (8-oxoG DNA glycosylase)-intact and OGG1-deficient mice (46). As OGG1 is the only DNA glycosylase that removes 8-oxoG in the initial step of base excision repair, OGG1-deficient cells would be expected to generate more mutations with UVA, if 8-oxoG contributed significantly to mutation formation with UVA. However, this was not found. In contrast to UVA mutagenesis, loss of OGG1 makes cells hypersensitive to killing by UVA (47). Apparently, oxidative DNA damage does contribute to cell killing by UVA, but not to mutation formation by UVA.

Taken together, the results of all these studies refute a prominent role of 8-oxoG in UVA mutagenesis and point to a significant contribution of pyrimidine dimers. Different model systems and UV sources are most likely to blame for the large differences in the published spectra of UVA-induced mutations. Model systems that use human skin cells and non-transformed cells have to be considered the most suitable. However, of these, it would be most interesting to study UVA mutagenesis in keratinocytes or melanocytes, as these are the types of cells that give rise to UV-induced tumours in humans. Unfortunately, these data are not available so far.

Mutations in UVA-irradiated skin

  1. Top of page
  2. Summary
  3. Formation of DNA damage and mutations following exposure to different wavelengths of UV light
  4. UVA also generates pyrimidine dimers
  5. Mutations induced by UVA in cultured cells
  6. Mutations in UVA-irradiated skin
  7. Mutations in UVA-induced tumours
  8. Are UVA-induced pyrimidine dimers more mutagenic than UVB-induced pyrimidine dimers?
  9. Clinical Relevance
  10. References

Limited data are available on what types of mutations are induced by UVA in skin. Persson et al. (48) sequenced p53 in single human skin keratinocytes repeatedly exposed to UVA. They found three cells with mutated p53, all of which carried G[RIGHTWARDS ARROW]T transversions, possibly pointing to 8-oxoG as the pre-mutagenic lesion in these experiments.

Ikehata et al. (49) sequenced UVA- and UVB-induced mutations in the skin of lacZ transgenic mice and found that the vast majority of both UVA- and UVB-induced mutations were C[RIGHTWARDS ARROW]T mutations, pointing to pyrimidine dimers as the premutagenic lesion. While this study is important, as it is the first one to describe a detailed spectrum of UVA-induced mutations in an in vivo model, it has been criticized for contaminating UVB in the UVA source possibly being responsible for the UVA-induced C[RIGHTWARDS ARROW]T mutations (43).

Mutations in UVA-induced tumours

  1. Top of page
  2. Summary
  3. Formation of DNA damage and mutations following exposure to different wavelengths of UV light
  4. UVA also generates pyrimidine dimers
  5. Mutations induced by UVA in cultured cells
  6. Mutations in UVA-irradiated skin
  7. Mutations in UVA-induced tumours
  8. Are UVA-induced pyrimidine dimers more mutagenic than UVB-induced pyrimidine dimers?
  9. Clinical Relevance
  10. References

Another way to approach the question on which types of DNA damage cause mutations with UVA is to study mutations in UVA-induced tumours. Van Kranen et al. (50) induced skin tumours (mainly squamous cell carcinomas) in albino hairless mice with UVA and sequenced the p53 gene in these tumours. As compared with UVB-induced tumours, immunostaining for mutated p53 was less common, less dense, and more irregular. Only 14% of the tumours demonstrated mutations in one of the p53 gene exons studied (vs. 60% in the UVB-induced tumours), indicating that p53 mutations may not play as pivotal a role in UVA as in UVB carcinogenesis. However, all of the confirmed p53 mutations in the UVA-induced tumours were C[RIGHTWARDS ARROW]T transitions, and all of these except one were located at mutation hotspots well-known from UVB-induced tumours. This clearly indicates a significant role of pyrimidine dimers in the formation of p53 mutations by UVA in mice. In addition, based on the complete absence of mutations typical for oxidative DNA damage, these data indicate that the involvement of oxidative DNA damage is highly unlikely.

As discussed above, melanoma may be a particularly UVA-induced tumour, and it is therefore worth asking the question as to what types of mutations are observed in melanomas. However, the genetic events that lead to the formation of melanoma are different from those that lead to the formation of squamous cell carcinomas, and it remains unclear which genes are mutated early in the photocarcinogenesis cascade of events in melanoma. For example p53 mutations are usually only a late event during melanoma progression. Only with low frequency have C[RIGHTWARDS ARROW]T and CC[RIGHTWARDS ARROW]TT mutations been found in the melanoma suppressor gene p16INK4a of primary melanomas (51), and it remains unclear whether alterations in that gene represent early or late events. Another tumour suppressor gene possibly involved early in melanoma is PTEN, and C[RIGHTWARDS ARROW]T mutations have been described in PTEN of melanomas (52). Taken together, these data also point to pyrimidine dimers playing a role in mutation events leading to melanoma, but a conclusion on whether these are UVA- or UVB-induced cannot be drawn.

A high frequency of T : A[RIGHTWARDS ARROW]A : T mutations at one particular site of BRAF has been described in malignant melanomas and melanocytic nevi (53). As these BRAF mutations have been found predominantly in melanomas from intermittently sun-exposed areas, but much less frequently in melanomas from unexposed areas or chronically UV-exposed areas, this type of mutation has been suggested to be UV-induced (54). However, this type of mutation is not located at a di-pyrimidine site and is not generated by any of the common types of UV-induced lesions. An unidentified, UV-induced (possibly particularly UVA-induced) thymine or adenine adduct might be responsible for these mutations. An alternative mechanism has been suggested, in which error-prone translesion synthesis of a nearby pyrimidine dimer could cause these BRAF mutations (55). This further underlines the difficulty of assigning a type of mutation to a particular type of pre-mutagenic lesion.

As described above, UV-induced mutation formation is most commonly thought to occur shortly after irradiation, through replication of UV-damaged DNA and incorporation of false bases opposite of DNA damage, or through faulty repair of UV-induced DNA damage. Dahle and Kvam (56), however, described that there is apparently also an alternative way of mutation formation. They described genome instability and delayed mutation formation in Chinese hamster fibroblasts 10–20 cell generations after irradiation with UVA or UVB, that this effect was more pronounced with UVA, as compared with UVB, and suggested this UV-induced genome instability as an alternative mechanism of UV-induced, in particular, UVA-induced mutation formation. The molecular mechanism of this UV-induced genome instability, however, has not been elucidated.

Are UVA-induced pyrimidine dimers more mutagenic than UVB-induced pyrimidine dimers?

  1. Top of page
  2. Summary
  3. Formation of DNA damage and mutations following exposure to different wavelengths of UV light
  4. UVA also generates pyrimidine dimers
  5. Mutations induced by UVA in cultured cells
  6. Mutations in UVA-irradiated skin
  7. Mutations in UVA-induced tumours
  8. Are UVA-induced pyrimidine dimers more mutagenic than UVB-induced pyrimidine dimers?
  9. Clinical Relevance
  10. References

When reflecting on putative mechanisms of UVA-induced mutation formation, several findings appear irreconcilable: on the one hand, the data that UVA induces more mutations per photoproduct than UVB and the divergence of the action spectra for formation of photoproducts and skin cancer in the UVA1 range (see discussion above; Fig. 1) support the hypothesis that a non-photoproduct type of DNA damage significantly contributes to UVA mutagenesis. On the other hand, available data on UVA-induced mutations (as reviewed above) provide support for the notion that DNA photoproducts are the main premutagenic lesion not only for UVB but also for UVA, and that non-photoproduct types of DNA damage are not major contributors to mutation formation with UVA.

We have suggested a possible explanation for this phenomenon (44). The fate of a given type of DNA damage, in essence, the question of whether it induces a mutation or not, depends not only on the DNA damage itself but also on the cellular reaction to the DNA damage. In fact, cells react in a variety of ways to DNA damage. Many of these DNA damage responses minimize the mutagenic consequences of DNA damage formation and they are tightly regulated by an intricate net of DNA damage-signaling pathways. A case in point is the tumour suppressor gene p53 (57), which, upon impairment of its function, results in a mutator phenotype, with e.g. a higher rate of mutation formation upon formation of DNA damage. The anti-mutagenic properties of p53 are manifold. Upon formation of DNA damage, it mediates a G1/S cell cycle arrest (58, 59). This prevents replication of damaged DNA, the most important circumstance under which mutations are formed, and provides additional time for DNA repair before replication. P53 also induces DNA repair genes and thereby facilitates improved repair of the DNA damage (60, 61). Recently, it was reported that p53 down-regulates the activity of the translesional DNA polymerase η to maintain a low mutagenic activity at the price of reduced damage bypass (62). Finally, with overwhelming DNA damage, p53 mediates apoptosis, which prevents survival of damaged cells that otherwise could live on with mutations. These functions in preventing mutation formation and maintaining genome stability have earned p53 the name ‘guardian of the genome' (63). Another case in point of the importance of cellular responses to DNA damage in the prevention of mutation and cancer formation in the skin is xeroderma pigmentosum. This DNA repair-deficient, skin cancer-prone genetic disorder demonstrates what happens when only one of the anti-mutagenic cellular defense mechanisms (DNA repair of UV-induced DNA damage) fails: a highly increased frequency of UV-induced tumours (64). It also demonstrates that most UV-induced DNA lesions are not translated into a mutation in repair-proficient cells.

We hypothesize that a UVA-induced DNA photoproduct is more mutagenic than a UVB-induced DNA photoproduct, because it is not accompanied by as much a protective, anti-mutagenic DNA damage response as with UVB. As one example of a profoundly weaker DNA damage response, we reported that UVA induces a much weaker and shorter-lasting activation (serine-15 phosphorylation) of p53 than UVB, using roughly equitoxic and solar available doses and the same doses as in the mutation studies (44). In line with our hypothesis, a less effective p53 activation with UVA may make mutation formation at a DNA photoproduct more likely, e.g. because of less cell cycle arrest and less activation of nucleotide excision repair, and may make survival of mutated cells more likely, due to less induction of apoptosis. And indeed, UVA was reported to produce a less effective intra-S-phase arrest in mouse keratinocytes than UVB (65).

Another example of a weaker DNA damage response is that UVA, unlike UVB, does not activate the Fanconi anaemia DNA damage response pathway, thought to mediate resolution of replication forks stalled at DNA photoproducts (25).

While much work has focused on the cellular responses to UV light, relatively few publications specifically compare UVA- vs. UVB-induced DNA damage responses. It is likely that there are many more differences in the cellular responses to UVA and UVB that differentially affect mutagenic outcomes. Furthermore, UVA might not simply induce a weaker damage response, but a qualitatively different one. For example oxidative damage, not only to DNA but also to proteins and membranes (which is much more readily generated by UVA), may modulate and possibly inhibit DNA damage responses. The relevance for this is exemplified by the description of a protein-repair enzyme, methionine sulphoxide reductase A, which repairs oxidized proteins, and is induced by UVA (66). In general, a comprehensive understanding of the cellular responses to UV in general, and to UVB vs. UVA in particular, remains elusive. Furthermore, complicating matters even further, DNA damage responses are likely to be different in different cell types.

Clinical Relevance

  1. Top of page
  2. Summary
  3. Formation of DNA damage and mutations following exposure to different wavelengths of UV light
  4. UVA also generates pyrimidine dimers
  5. Mutations induced by UVA in cultured cells
  6. Mutations in UVA-irradiated skin
  7. Mutations in UVA-induced tumours
  8. Are UVA-induced pyrimidine dimers more mutagenic than UVB-induced pyrimidine dimers?
  9. Clinical Relevance
  10. References

If the hypothesis that UVA-induced DNA photoproducts are more mutagenic than UVB-induced ones is substantiated, such new insights into how UVA contributes to UV-induced mutation formation and skin carcinogenesis would clinically be most relevant for UV-exposure situations with pure or almost pure UVA. During mid-day sun exposure, the prominent effects of the UVB portion of the solar spectrum are expected to induce the protective damage response and thereby greatly minimize the effects of the relatively small contribution of UVA to photoproduct formation. However, pure or almost pure UVA exposures do occur: (1) during sun exposure through window glass (which completely blocks UVB, but not UVA); (2) during the use of non-broad-spectrum sunscreen formulations that block UVB very effectively, but not, or to a much lesser degree UVA (even in broad-spectrum sunscreens, UVA is filtered less effectively than UVB) (67); (3) in sun-tanning parlors (which use high-dose UVA emitters to prevent sunburning from UVB); and (4) in UVA phototherapy, which is increasingly developed for treatment of various inflammatory skin conditions, including atopic dermatitis or scleroderma (68, 69). In these situations, the UVA alone would generate much less of a protective DNA damage response, and would result in greater mutation formation at the UVA-induced photoproducts. As pure UVA exposure situations are a phenomenon of modern civilization, evolution might not have developed sufficiently protective responses to them. A detailed understanding of the mechanisms underlying UVA mutagenesis is therefore of utmost importance to develop better strategies for photo-protection, risk assessment of artificial UV sources, and skin cancer prevention.

References

  1. Top of page
  2. Summary
  3. Formation of DNA damage and mutations following exposure to different wavelengths of UV light
  4. UVA also generates pyrimidine dimers
  5. Mutations induced by UVA in cultured cells
  6. Mutations in UVA-irradiated skin
  7. Mutations in UVA-induced tumours
  8. Are UVA-induced pyrimidine dimers more mutagenic than UVB-induced pyrimidine dimers?
  9. Clinical Relevance
  10. References
  • 1
    Rünger TM. Ultraviolet light. In: BologniaJL, JorizzoJL, RapiniRP, eds. Dermatology. London: Mosby, 2003; 13531363.
  • 2
    Stary A, Sarasin A. Ultraviolet A- and singlet oxygen-induced mutation spectra. Methods Enzymol 2000; 319: 153165.
  • 3
    Rünger TM. The role of UVA in the pathogenesis of melanoma and non-melanoma skin cancer. Photodermatol Photoimmunol Photomed 1999; 15: 212216.
  • 4
    Wang SW, Setlow RB, Berwick M, et al. Ultraviolet A and melanoma: a review. J Am Acad Dermatol 2001; 44: 837846.
  • 5
    Moan J, Dahlbeck A, Setlow RB. Epidemiological support for an hypothesis for melanoma induction indicating a role for UVA radiation. Photochem Photobiol 1999; 70: 243247.
  • 6
    Gallagher RP, Spinelli JJ, Lee TK, Gallagher RP, Spinelli JJ, Lee TK. Tanning beds, sunlamps, and risk of cutaneous malignant melanoma. Cancer Epidemiol Biomarkers Prevention 2005; 14: 562566.
  • 7
    Veierod MB, Weiderpass E, Thorn M, et al. A prospective study of pigmentation, sun exposure, and risk of cutaneous malignant melanoma in women. J Natl Cancer Inst 2003; 95: 15301538.
  • 8
    Higgins EM, Du Vivier AW. Possible induction of malignant melanoma by sunbed use. Clin Exp Dermatol 1992; 17: 357359.
  • 9
    Setlow RB, Grist E, Thompson K, Woodhead AD. Wavelengths effective in induction of malignant melanoma. Proc Natl Acad Sci USA 1993; 90: 66666670.
  • 10
    Ley RD. Ultraviolet radiation A-induced precursors of cutaneous melanoma in monodelphis domestica. Cancer Res 1997; 57: 36823684.
  • 11
    Autier P, Doré JF, Schifflers E. Melanoma and use of sunscreens: an EORTC case-control study in Germany, Belgium, and France. The EORTC melanoma cooperative group. Int J Cancer 1995; 61: 749755.
  • 12
    De Fabo EC, Noonan FP, Fears T, Merlino G. Ultraviolet B but not ultraviolet A radiation initiates melanoma. Cancer Res 2004; 64: 63726376.
  • 13
    Ziegler A, Leffell DJ, Kunala S, et al. Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers. Proc Natl Acad Sci USA 1993; 90: 42164220.
  • 14
    Wikondahl NM, Brash DE. Ultraviolet radiation induced signature mutations in photocarcinogenesis. J Invest Dermatol Symp Proc 1999; 4: 610.
  • 15
    Le Clerc JE, Borden A, Lawrence CW. The thymine-thymine pyrimidine-pyrimidone (6–4) ultraviolet light photoproduct is highly mutagenic and specifically induces 3′ thymine-to-cytosine transitions in Escherichia coli. Proc Natl Acad Sci USA 1991; 88: 96859689.
  • 16
    Piette J, Merville-Louis MP, Decuyper J. Damages induced in nucleic acids by photosensitization. Photochem Photobiol 1986; 44: 793802.
  • 17
    Kielbassa C, Roza L, Epe B. Wavelength dependence of oxidative DNA damage induced by UV and visible light. Carcinogenesis 1997; 18: 811816.
  • 18
    Darr D, Fridovich I. Free radicals in cutaneous biology. J Invest Dermatol 1994; 102: 671675.
  • 19
    Cheng KC, Cahill DS, Kasai H, Nishimura S, Loeb LA. 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G to T and A to C substitutions. J Biol Chem 1992; 267: 166172.
  • 20
    Epe B. Genotoxicity of singlet oxygen. Chem Biol Interact 1991; 80: 239260.
  • 21
    Kuluncsics Z, Perdiz D, Brulay E, Muel B, Sage E. Wavelengths dependence of ultraviolet-induced DNA damage distribution: involvement of direct or indirect mechanisms and possible artefacts. J Photochem Photobiol B 1999; 49: 7180.
  • 22
    Greene KF, Budzinski EE, Iijima H, et al. Assessment of DNA damage at the dimer level: measurement of the formamide lesion. Br J Cancer 2007; 167: 146151.
  • 23
    Essigmann JM, Basu AK, Loechler EL. Mutagenic specificity of alkylated and oxidized DNA bases as determined by site-specific mutagenesis. Ann Istit Sup San 1989; 25: 155161.
  • 24
    Rünger TM, Möller K, Jung T, Dekant B. DNA damage formation, DNA repair, and survival after exposure of DNA repair-proficient and nucleotide excision repair-deficient human lymphoblasts to UVA1 and UVB. Int J Radiat Biol 2000; 76: 789797.
  • 25
    Dunn J, Potter M, Rees A, Rünger TM. Activation of the Fanconi anemia/BRCA pathway and recombination repair in the cellular response to solar UV. Cancer Res 2006; 66: 1114011146.
  • 26
    Freeman SE, Gange RW, Sutherland JC, Matzinger EA, Sutherland BM. Production of pyrimidine dimers in DNA of human skin exposed in situ to UVA radiation. J Invest Dermatol 1987; 88: 430433.
  • 27
    Matsunaga T, Hieda K, Nikaido O. Wavelength dependent formation of thymine dimers and (6–4) photoproducts in DNA by monochromatic ultraviolet light ranging from 150 to 365 nm. Photochem Photobiol 1991; 54: 403410.
  • 28
    Ley RD, Fourtanier A. UVA1-induced edema and pyrimidine dimers in murine skin. Photochem Photobiol 2000; 72: 485487.
  • 29
    Young AR, Potten CS, Nikaido O, et al. Human melanocytes and keratinocytes exposed to UVB or UVA in vivo show comparable levels of thymine dimers. J Invest Dermatol 1998; 111: 936940.
  • 30
    Douki T, Perdiz D, Grof P, et al. Oxidation of guanine in cellular DNA by solar UV radiation: biological role. Photochem Photobiol 1999; 70: 184190.
  • 31
    Courdavault S, Baudouin C, Charveron M, Favier A, Cadet J, Douki T. Larger yield of cyclobutane dimers than 8-oxo-7,8-dihydroguanine in the DNA of UVA-irradiated human skin cells. Mutat Res 2004; 556: 135142.
  • 32
    Douki T, Reynaud-Angelin A, Cadet J, Sage E. Bipyrimidine photoproducts rather than oxidative lesions are the main type of DNA damage involved in the genotoxic effect of solar UVA radiation. Biochem 2003; 42: 92219226.
  • 33
    Rochette PJ, Therrien JP, Drouin R, et al. UVA-induced cyclobutane pyrimidine dimers form predominantly at thymine–thymine dipyrimidines and correlate with the mutation spectrum in rodent cells. Nucl Acids Res 2003; 31: 27862794.
  • 34
    De Gruijl FR, Sterenborg HJ, Forbes PD, et al. Wavelength dependence of skin cancer induction by ultraviolet irradiation of albino hairless mice. Cancer Res 1993; 53: 5360.
  • 35
    De Gruijl FR. Photocarcinogenesis: UVA vs UVB. Methods Enzymol 2000; 319: 359366.
  • 36
    Enninga IC, Groenendijk RTL, Filon AR, Van Zeeland AA, Simons JWIM. The wavelength dependence of UV-induced pyrimidine dimer formation, cell killing and mutation induction in human diploid skin fibroblasts. Carcinogenesis 1986; 7: 18291836.
  • 37
    Reid TM, Loeb LA. Tandem double CC[RIGHTWARDS ARROW]TT mutations are produced by reactive oxygen species. Proc Natl Acad Sci USA 1993; 90: 39043907.
  • 38
    Drobetsky EA, Turcotte J, Chateauneuf A. A role for ultraviolet A in solar mutagenesis. Proc Natl Acad Sci USA 1995; 92: 23502354.
  • 39
    Hanawalt PC. Revisiting the rodent repairadox. Environ Mol Mutagenesis 2001; 38: 8996.
  • 40
    Finlay CA. p53 loss of function: implications for the processes of immortalization and tumorigenesis. Bioessays 1992; 14: 557560.
  • 41
    Tiemann F, Deppert W. Stabilization of the tumor suppressor p53 during cellular transformation by simian virus 40: influence of viral and cellular factors and biological consequences. J Virol 1994; 68: 28692878.
  • 42
    Robert C, Mueller H, Benoit A, Dubertret L, Sarasin A, Stary A. Cell survival and shuttle vector mutagenesis induced by ultraviolet A and ultraviolet B radiation in a human cell line. J Invest Dermatol 1996; 106: 721728.
  • 43
    Besaratinia A, Synold TW, Xi B, Pfeifer GP. G-to-T transversions and small tandem base deletions are the hallmark of mutations induced by ultraviolet A radiation in mammalian cells. Biochemistory 2004; 43: 81698177.
  • 44
    Kappes UP, Luo D, Potter M, Schulmeister K, Rünger TM. Short- and long-wave ultraviolet light (UVB and UVA) induce similar mutations in human skin cells. J Invest Dermatol 2006; 126: 667675.
  • 45
    McGregor WG, Chen RH, Lukash L, Maher VM, McCormick JJ. Cell cycle-dependent strand bias for UV-induced mutations in the transcribed strand of excision repair-proficient human fibroblasts but not in repair-deficient cells. Mol Cell Biol 1991; 11: 1934.
  • 46
    Kappes UP, Rünger TM. No major role for 7,8-dihydro-8-oxoguanine in ultraviolet light-induced mutagenesis. Radiat Res 2005; 164: 440445.
  • 47
    Kim KJ, Chakrabarty I, Li GZ, Grösch S, Kaina B, Rünger TM. Modulation of base excision repair alters cellular sensitivity to UVA1, but not to UVB. Photochem Photobiol 2002; 75: 507512.
  • 48
    Persson AE, Edstrom DW, Backvall H, et al. The mutagenic effect of ultraviolet-A1 on human skin demonstrated by sequencing the p53 gene in single keratinocytes. Photodermatol Photoimmunol Photomed 2002; 18: 287293.
  • 49
    Ikehata H, Kudo H, Masuda T, Ono T. UVA induces C to T transitions at methyl-CpG-associated dipyrimidine sites in mouse skin epidermis more frequently than UVB. Mutagenesis 2003; 18: 511519.
  • 50
    Van Kranen HJ, De Laat A, Van De Ven J, et al. Low incidence of p53 mutations in UVA (365-nm)-induced skin tumors in hairless mice. Cancer Res 1997; 57: 12381240.
  • 51
    Peris K, Chimenti S, Fargnoli MC, Valeri P, Kerl H, Wolf P. UV fingerprint CDKN2a but no p14ARF mutations in sporadic melanomas. J Invest Dermatol 1999; 112: 825826.
  • 52
    Wang Y, DiGiovanna JJ, Stern J, Hornyak TJ, Raffeld M, Kraemer KH. UV-signature mutations in melanomas from xeroderma pigmentosum patients (abstract). J Invest Dermatol 2007; 127: S150.
  • 53
    Pollock PM, Harper UL, Hansen KS, et al. High frequency of BRAF mutations in nevi. Nat Genet 2003; 33: 1920.
  • 54
    Maldonado JL, Fridlyand J, Patel H, et al. Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst 2003; 95: 18781890.
  • 55
    Thomas NE, Berwick M, Cordeiro-Stono M. Could BRAF mutations in melanocytic lesions arise from DNA damage induced by ultraviolet light? J Invest Dermatol 2006; 126: 16931696.
  • 56
    Dahle J, Kvam E. Induction of delayed mutations and chromosomal instability in fibroblasts after UVA-, UVB-, and X-radiation. Cancer Res 2003; 63: 14641469.
  • 57
    Decraene D, Agostinis P, Pupe A, De Haes P, Garmyn M. Acute response of human skin to solar radiation: regulation and function of the p53 protein. J Photochem Photobiol B 2001; 63: 7883.
  • 58
    Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, et al. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Ann Rev Biochem 2004; 73: 3985.
  • 59
    Decraene D, Agostinis P, Pupe A, et al. Acute response of human skin to solar radiation: regulation and function of the p53 protein. J Photochem Photobiol B 2001; 63: 7883.
  • 60
    Smith ML, Seo YR. p53 regulation of DNA excision repair pathways. Mutagenesis 2002; 17: 149156.
  • 61
    Hanawalt PC, Hanawalt PC. Subpathways of nucleotide excision repair and their regulation. Oncogene 2002; 21: 89498956.
  • 62
    Avkin S, Sevilya Z, Toube L, et al. p53 and p21 regulate error-prone DNA repair to yield a lower mutation load. Mol Cell 2006; 22: 407413.
  • 63
    Lane DP, Lane DP. Cancer. p53, guardian of the genome. Nature 1992; 358: 1516.
  • 64
    Rünger TM, DiGiovanna JJ, Kraemer KH. Hereditary disorders of genome instability and DNA repair. In: WolffK, GoldsmithLA, KatzSI, GilchrestBA, PallerAS, LeffellDJ, eds. Fitzpatrick's Dermatology in General Medicine. New York: McGraw-Hill Medical, 2007.
  • 65
    De Laat A, Kroon ED, De Gruijl FR, De Laat A, Kroon ED, DeGruijl FR. Cell cycle effects and concomitant p53 expression in hairless murine skin after longwave UVA (365 nm) irradiation: a comparison with UVB irradiation. Photochem Photobiol 1997; 65: 730735.
  • 66
    Ogawa F, Sander CS, Hansel A, et al. The repair enzyme peptide methionine-S-sulfoxide reductase is expressed in human epidermis and upregulated by UVA radiation. J Invest Dermatol 2006; 126: 11281134.
  • 67
    Lim HW, Draelos ZD, Rigel DS, Rünger TM. Shedding light on complete UV-protection. Cosm Dermatol 2006; 19 S3: 38.
  • 68
    Morita A, Kobayashi K, Isomura I, et al. Ultraviolet A1 (340–400 nm) phototherapy for scleroderma in systemic sclerosis. J Am Acad Dermatol 2000; 43: 670674.
  • 69
    Krutmann J, Diepgen TL, Luger TA, et al. High-dose UVA1 therapy for atopic dermatitis: results of a multicenter trial. J Am Acad Dermatol 1998; 38: 589593.
  • 70
    Young AR, Chadwick CA, Harrison GI, Nikaido O, Ramsden J, Potten CS. The similarity of action spectra for thymine dimers in human epidermis and erythema suggests that DNA is the chromophore for erythema. J Invest Dermatol 1998; 111: 982988.