Mutations induced by ultraviolet light

doi:10.1016/j.mrfmmm.2004.06.057

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis

Volume 571, Issues 1–2, 1 April 2005, Pages 19-31

https://doi.org/10.1016/j.mrfmmm.2004.06.057 Get rights and content

Abstract

The different ultraviolet (UV) wavelength components, UVA (320–400 nm), UVB (280–320 nm), and UVC (200–280 nm), have distinct mutagenic properties. A hallmark of UVC and UVB mutagenesis is the high frequency of transition mutations at dipyrimidine sequences containing cytosine. In human skin cancers, about 35% of all mutations in the p53 gene are transitions at dipyrimidines within the sequence 5′-TCG and 5′-CCG, and these are localized at several mutational hotspots. Since 5′-CG sequences are methylated along the p53 coding sequence in human cells, these mutations may be derived from sunlight-induced pyrimidine dimers forming at sequences that contain 5-methylcytosine. Cyclobutane pyrimidine dimers (CPDs) form preferentially at dipyrimidines containing 5-methylcytosine when cells are irradiated with UVB or sunlight. In order to define the contribution of 5-methylcytosine to sunlight-induced mutations, the lacI and cII transgenes in mouse fibroblasts were used as mutational targets. After 254 nm UVC irradiation, only 6–9% of the base substitutions were at dipyrimidines containing 5-methylcytosine. However, 24–32% of the solar light-induced mutations were at dipyrimidines that contain 5-methylcytosine and most of these mutations were transitions. Thus, CPDs forming preferentially at dipyrimidines with 5-methylcytosine are responsible for a considerable fraction of the mutations induced by sunlight in mammalian cells. Using mouse cell lines harboring photoproduct-specific photolyases and mutational reporter genes, we showed that CPDs (rather than 6-4 photoproducts or other lesions) are responsible for the great majority of UVB-induced mutations. An important component of UVB mutagenesis is the deamination of cytosine and 5-methylcytosine within CPDs. The mutational specificity of long-wave UVA (340–400 nm) is distinct from that of the shorter wavelength UV and is characterized mainly by G to T transversions presumably arising through mechanisms involving oxidized DNA bases. We also discuss the role of DNA damage-tolerant DNA polymerases in UV lesion bypass and mutagenesis.

Section snippets

UV-induced DNA photoproducts

Irradiation of DNA or cells with ultraviolet light (UV) induces the formation of several types of mutagenic DNA lesions. The most frequent lesions induced by UVB or UVC radiation are the cis-syn cyclobutane pyrimidine dimers (CPDs) and the pyrimidine (6-4) pyrimidone photoproducts [(6-4) photoproducts; (6-4)PPs]. Several minor photoproducts such as purine dimers and pyrimidine mono-adducts are also formed [1]. CPDs are formed between the 5,6 bonds of any two adjacent pyrimidine bases. (6-4)PPs

UV and skin cancer mutations

Skin cancer is the most common tumor diagnosed in the United States and the numbers of both non-melanoma and melanoma skin cancers have increased dramatically over the last few decades [11], [12]. The available epidemiological evidence indicates clearly that solar UV irradiation is associated with skin cancer [13].

Mutations in cancer-relevant genes are produced by those UV photoproducts that are not repaired before DNA replication. Thus, DNA excision repair systems play an important role in

UV and melanoma

The causative relationship between UVB exposure and non-melanoma skin cancer is well documented [27], [28]. The link between sunlight exposure and melanoma is somewhat less compelling but still apparent. Melanoma, the most lethal form of skin cancer, shows a dramatic rate of increase worldwide and causes over 7000 deaths each year in the United States [29]. There is epidemiological evidence suggesting that a history of sunburn and intermittent exposure to strong sunlight, particularly during

The DNA damage spectrum produced by simulated sunlight

Experimental systems for determining the levels and sequence dependence of photoproduct formation in DNA have often used high doses of short wave (UVC) irradiation. We have re-assessed this issue by using DNA sequencing technologies and different doses of UVC as well as more physiologically relevant doses of solar irradiation emitted from a solar UV simulator [3]. We used UV damage endonuclease in combination with CPD photolyase for specific detection of (6-4) photoproducts and T4 endonuclease

UVB mutagenesis

UV mutagenesis is characterized by a high frequency of transition mutations at dipyrimidine sequences containing cytosine bases implicating dimeric pyrimidine photoproducts containing cytosine as the mutagenic lesions (reviewed in [1], [50]). However, the precise mechanism of how UV light causes C to T transition mutations at cytosine-containing dipyrimidine sites is still unknown. The CPD is believed to be the major mutagenic lesion in mammalian cells owing to its high levels of induction,

5-Methylcytosine and UVB mutagenesis

It has long been known that dipyrimidines containing cytosines are the preferred targets for UV-induced mutagenesis [60], [61]. More recently, it has been recognized that 5-methylcytosine plays an even more important role in UVB-induced mutations. 5-Methylcytosines are present almost exclusively at CpG dinucleotides in mammalian cells. These sequences are known mutational hotspots in cancer-relevant genes and are often mutated in genes associated with human genetic diseases. The increased

Cyclobutane pyrimidine dimers are responsible for the majority of mutations induced by UVB irradiation in mammalian cells

The most prevalent DNA lesions induced by UVB are the CPDs and the (6-4)PPs. It has been a long-lasting debate as to which of these photoproducts is responsible for UV-induced mutations in mammalian cells. We have introduced photoproduct-specific DNA photolyases into a mouse cell line carrying the transgenic mutational reporter genes lacI and cII. Exposure of the photolyase-expressing cell lines to photoreactivating light resulted in almost complete repair of either CPDs or (6-4) photoproducts

Deamination of cytosine and 5-methylcytosines within cyclobutane pyrimidine dimers is an important component of UVB mutagenesis

UVB mutagenesis is characterized by an abundance of C to T and 5-methylcytosine to T transitions at dipyrimidine sequences. It is not however known how these mutations might arise mechanistically. One hypothesis is that UV-induced mutations occur only after deamination of the cytosine or the 5-methylcytosine within the pyrimidine dimer [25], [68], [70], [71], [72], [73], [74], [75], [76]. Deamination of cytosines within CPDs does occur at a significant rate in human cells [76]. It is of

UV lesion bypass

The low frequency of mutations at 5′-TT sequences in UV-irradiated cells is likely due to the action of DNA polymerase η (POLH), which correctly bypasses these lesions. DNA polymerase η is encoded by the RAD30 gene in yeast and by the POLH (XPV) gene in humans [51], [77], [78]. Two models of UV mutagenesis are conceivable to explain the preponderance of C to T transition mutations at dipyrimidine sites (Fig. 2). One pathway involves direct lesion bypass by a DNA polymerase that incorporates

UVA mutagenesis

The genotoxicity of UVA has most commonly been ascribed to endogenous photosynthesizers causing reactive oxygen species-mediated induction of DNA damage [6], [7], [9], [10], [28], [99], [100], [101], [102]. However, more recently, it has been reported that UVA can induce CPDs in rodent cells [4], [5], [103]. The poor absorbance of UVA by DNA itself favors the idea that type I (direct reaction) or type II (indirect through reaction of the excited photosensitizer molecule with oxygen)

Acknowledgement

This work has been supported by the National Institute of Environmental Health Sciences (grant ES06070).

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¹: Present address: Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.

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ReviewMutations induced by ultraviolet light

Abstract

Section snippets

UV-induced DNA photoproducts

UV and skin cancer mutations

UV and melanoma

The DNA damage spectrum produced by simulated sunlight

UVB mutagenesis

5-Methylcytosine and UVB mutagenesis

Cyclobutane pyrimidine dimers are responsible for the majority of mutations induced by UVB irradiation in mammalian cells

Deamination of cytosine and 5-methylcytosines within cyclobutane pyrimidine dimers is an important component of UVB mutagenesis

UV lesion bypass

UVA mutagenesis

Acknowledgement

J. Mol. Biol.

J. Photochem. Photobiol. B

J. Am. Acad. Dermatol.

Cancer Cell

Mutat. Res.

Trends Genet.

Eur. J. Cancer

Lancet

Biochim. Biophys. Acta

J. Am. Acad. Dermatol.

J. Biol. Chem.

J. Mol. Biol.

J. Biol. Chem.

J. Mol. Biol.

J. Mol. Biol.

J. Mol. Biol.

J. Biol. Chem.

J. Biol. Chem.

Mutat. Res.

J. Mol. Biol.

Mol. Cell

J. Biol. Chem.

Mutat. Res.

DNA Repair

J. Biol. Chem.

J. Invest. Dermatol.

Formation and processing of UV photoproducts: effects of DNA sequence and chromatin environment

Photochem. Photobiol.

The biology of the (6-4) photoproduct

Photochem. Photobiol.

UVA-induced cyclobutane pyrimidine dimers form predominantly at thymine–thymine dipyrimidines and correlate with the mutation spectrum in rodent cells

Nucleic Acids Res.

Bipyrimidine photoproducts rather than oxidative lesions are the main type of DNA damage involved in the genotoxic effect of solar UVA radiation

Biochemistry

Effects of UV and visible radiation on DNA-final base damage

Biol. Chem.

Wavelength dependence of oxidative DNA damage induced by UV and visible light

Carcinogenesis

Induction of oxidative DNA base damage in human skin cells by UV and near visible radiation

Carcinogenesis

Induction of 8-oxo-7,8-dihydro-2′-deoxyguanosine by ultraviolet radiation in calf thymus DNA and HeLa cells

Photochem. Photobiol.

Molecular mechanisms of ultraviolet radiation carcinogenesis

Photochem. Photobiol.

In vivo mapping of a DNA adduct at nucleotide resolution: detection of pyrimidine (6-4) pyrimidone photoproducts by ligation-mediated polymerase chain reaction

Proc. Natl. Acad. Sci. U.S.A.

Binding of transcription factors creates hot spots for UV photoproducts in vivo

Mol. Cell. Biol.

Cell cycle-independent removal of UV-induced pyrimidine dimers from the promoter and the transcription initiation domain of the human CDC2 gene

Nucleic Acids Res.

Slow repair of pyrimidine dimers at p53 mutation hotspots in skin cancer

Science

DNA repair domains within a human gene: selective repair of sequences near the transcription initiation site

EMBO J.

Lack of gene- and strand-specific DNA repair in RNA polymerase III transcribed human tRNA genes

Mol. Cell. Biol.

A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma

Proc. Natl. Acad. Sci. U.S.A.

Specific UV-induced mutation spectrum in the p53 gene of skin tumors from DNA-repair-deficient xeroderma pigmentosum patients

Proc. Natl. Acad. Sci. U.S.A.

Mutation hot spots due to sunlight in the p53 gene of nonmelanoma skin cancers

Proc. Natl. Acad. Sci. U.S.A.

TP53 mutations in human skin cancers

Hum. Mutat.

Sunlight induces pyrimidine dimers preferentially at 5-methylcytosine bases

Cancer Res.

Review
Mutations induced by ultraviolet light