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ACS Omega Sep 2022Melanoma is a lethal type of skin tumor that has been linked with sunlight exposure chiefly in fair-skinned human populations. Wavelengths from the sun that can reach... (Review)
Review
Melanoma is a lethal type of skin tumor that has been linked with sunlight exposure chiefly in fair-skinned human populations. Wavelengths from the sun that can reach the earth's surface include UVA radiation (320-400 nm) and UVB radiation (280-320 nm). UVB effectively induces the formation of dimeric DNA photoproducts, preferentially the cyclobutane pyrimidine dimers (CPDs). The characteristic UVB signature mutations in the form of C to T mutations at dipyrimidine sequences are prevalent in melanoma tumor genomes and have been ascribed to deamination of cytosines within CPDs before DNA polymerase bypass. However, evidence from epidemiological, animal, and other experimental studies also suggest that UVA radiation may participate in melanoma formation. The DNA damage relevant for UVA includes specific types of CPDs at TT sequences and perhaps oxidative DNA damage to guanine, both induced by direct or indirect, photosensitization-mediated chemical and biophysical processes. We summarize the evidence for a potential role of UVA in melanoma and discuss some of the mechanistic pathways of how UVA may induce mutagenesis in melanocytes.
PubMed: 36157735
DOI: 10.1021/acsomega.2c04424 -
PLoS Genetics Sep 2022Nucleotide excision repair is the primary repair mechanism that removes UV-induced DNA lesions in placentals. Unrepaired UV-induced lesions could result in mutations...
Nucleotide excision repair is the primary repair mechanism that removes UV-induced DNA lesions in placentals. Unrepaired UV-induced lesions could result in mutations during DNA replication. Although the mutagenesis of pyrimidine dimers is reasonably well understood, the direct effects of replication fork progression on nucleotide excision repair are yet to be clarified. Here, we applied Damage-seq and XR-seq techniques and generated replication maps in synchronized UV-treated HeLa cells. The results suggest that ongoing replication stimulates local repair in both early and late replication domains. Additionally, it was revealed that lesions on lagging strand templates are repaired slower in late replication domains, which is probably due to the imbalanced sequence context. Asymmetric relative repair is in line with the strand bias of melanoma mutations, suggesting a role of exogenous damage, repair, and replication in mutational strand asymmetry.
Topics: DNA; DNA Damage; DNA Repair; DNA Replication; HeLa Cells; Humans; Pyrimidine Dimers; Ultraviolet Rays
PubMed: 36155646
DOI: 10.1371/journal.pgen.1010426 -
Pigment Cell & Melanoma Research Jan 2023Melanin is a free-radical scavenger, antioxidant, and broadband absorber of ultraviolet (UV) radiation which protects the skin from environmental carcinogenesis....
Melanin is a free-radical scavenger, antioxidant, and broadband absorber of ultraviolet (UV) radiation which protects the skin from environmental carcinogenesis. However, melanin synthesis and UV-induced reactive melanin species are also implicated in melanocyte genotoxicity. Here, we attempted to reconcile these disparate functions of melanin using a UVB-sensitive, NRAS-mutant mouse model, TpN. We crossed TpN mice heterozygous for an inactivating mutation in Tyrosinase to produce albino and black littermates on a C57BL/6J background. These animals were then exposed to a single UVB dose on postnatal day three when keratinocytes in the skin have yet to be melanized. Approximately one-third (35%) of black mice were protected from UVB-accelerated tumor formation. However, melanoma growth rates, tumor mutational burdens, and gene expression profiles were similar in melanomas from black and albino mice. Skin from albino mice contained more cyclobutane pyrimidine dimer (CPD) positive cells than black mice 1-h post-irradiation. However, this trend gradually reversed over time with CPDs becoming more prominent in black than albino melanocytes at 48 h. These results show that in the absence of epidermal pigmentation, melanocytic melanin limits the tumorigenic effects of acute UV exposure but fails to protect melanocytes from UVB-induced mutagenesis.
Topics: Mice; Animals; Melanins; Skin Neoplasms; Mice, Inbred C57BL; Melanocytes; Melanoma; Ultraviolet Rays; Mutagenesis
PubMed: 36148789
DOI: 10.1111/pcmr.13070 -
Molecules (Basel, Switzerland) Sep 2022The photolyase family consists of flavoproteins with enzyme activity able to repair ultraviolet light radiation damage by photoreactivation. DNA damage by the formation... (Review)
Review
The photolyase family consists of flavoproteins with enzyme activity able to repair ultraviolet light radiation damage by photoreactivation. DNA damage by the formation of a cyclobutane pyrimidine dimer (CPD) and a pyrimidine-pyrimidone (6-4) photoproduct can lead to multiple affections such as cellular apoptosis and mutagenesis that can evolve into skin cancer. The development of integrated applications to prevent the negative effects of prolonged sunlight exposure, usually during outdoor activities, is imperative. This study presents the functions, characteristics, and types of photolyases, their therapeutic and cosmetic applications, and additionally explores some photolyase-producing microorganisms and drug delivery systems.
Topics: DNA Repair; Deoxyribodipyrimidine Photo-Lyase; Flavoproteins; Pyrimidine Dimers; Pyrimidines; Pyrimidinones; Ultraviolet Rays
PubMed: 36144740
DOI: 10.3390/molecules27185998 -
Biophysical Reviews Aug 2022DNA glycosylases are DNA repair enzymes capable of removing damaged nitrogenous bases, including those formed as a result of UV irradiation with sunlight (approximately... (Review)
Review
UNLABELLED
DNA glycosylases are DNA repair enzymes capable of removing damaged nitrogenous bases, including those formed as a result of UV irradiation with sunlight (approximately 300-400 нм). DNA glycosylases are common not only among bacteria, archaea, and eukaryotes, but some groups of viruses can also encode them. The best-known viral glycosylase is endonuclease V (DenV, Pdg-T4) of Escherichia virus T4, the main substrate of which is cyclobutane pyrimidine dimers. DenV is isolated separately from other large families of glycosylases; it is quite common in nature and has homologs in a number of other viruses and even bacteria. However, the ways of its origin are poorly understood. The best-known DenV homolog is the glycosylase of Chlorella virus strain, PBCV-1 (Cv-pdg). This review contains the main known data on the structure and mechanism of operation of DenV and its homologs. The issues of biological importance and distribution of the enzyme and its homologs among viruses are considered and supplemented separately.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s12551-022-00972-4.
PubMed: 36124272
DOI: 10.1007/s12551-022-00972-4 -
Toxicology and Applied Pharmacology Nov 2022Arsenite interferes with DNA repair protein function resulting in the retention of UV-induced DNA damage. Accumulated DNA damage promotes replication stress which is...
Arsenite interferes with DNA repair protein function resulting in the retention of UV-induced DNA damage. Accumulated DNA damage promotes replication stress which is bypassed by DNA damage tolerance pathways such as translesion synthesis (TLS). Rad18 is an essential factor in initiating TLS through PCNA monoubiquitination and contains two functionally and structurally distinct zinc fingers that are potential targets for arsenite binding. Arsenite treatment displaced zinc from endogenous Rad18 protein and mass spectrometry analysis revealed arsenite binding to both the Rad18 RING finger and UBZ domains. Consequently, arsenite inhibited Rad18 RING finger dependent PCNA monoubiquitination and polymerase eta recruitment to DNA damage in UV exposed keratinocytes, both of which enhance the bypass of cyclobutane pyrimidine dimers during replication. Further analysis demonstrated multiple effects of arsenite, including the reduction in nuclear localization and UV-induced chromatin recruitment of Rad18 and its binding partner Rad6, which may also negatively impact TLS initiation. Arsenite and Rad18 knockdown in UV exposed keratinocytes significantly increased markers of replication stress and DNA strand breaks to a similar degree, suggesting arsenite mediates its effects through Rad18. Comet assay analysis confirmed an increase in both UV-induced single-stranded DNA and DNA double-strand breaks in arsenite treated keratinocytes compared to UV alone. Altogether, this study supports a mechanism by which arsenite inhibits TLS through the altered activity and regulation of Rad18. Arsenite elevated the levels of UV-induced replication stress and consequently, single-stranded DNA gaps and DNA double-strand breaks. These potentially mutagenic outcomes support a role for TLS in the cocarcinogenicity of arsenite.
Topics: Arsenic; Arsenites; Chromatin; DNA Damage; DNA Repair; DNA Replication; DNA, Single-Stranded; Proliferating Cell Nuclear Antigen; Pyrimidine Dimers; Ubiquitin-Protein Ligases; Ubiquitination; Zinc
PubMed: 36087615
DOI: 10.1016/j.taap.2022.116230 -
Clinical, Cosmetic and Investigational... 2022Ultraviolet B (UVB) exposure leads to formation of photoproducts leading to cellular damage. Prevention using sunscreen can sometimes be inadequate and can be an...
Topical Curcumin as Chemoprotector Against Photoproducts Production: The Role of Cyclobutyl Pyrimidine Dimers, 8-Hydroxy2'Deoxyguanosine Expression and Epidermal Hyperplasia in Acute and Chronic UVB-Induced Mice.
BACKGROUND
Ultraviolet B (UVB) exposure leads to formation of photoproducts leading to cellular damage. Prevention using sunscreen can sometimes be inadequate and can be an economic burden. Recent studies have suggested the photoprotective effect of curcumin.
OBJECTIVE
To examine the acute and chronic photoprotective effect of topical curcumin, using cyclobutyl pyrimidine dimers (CPD) and 8-hydroxy2'deoxyguanosine (8-OHdG) expression as markers of DNA-induced damage, and epidermal hyperplasia on UVB-induced mice.
METHODS
Three treatment groups were established. Group A (negative control) consisted of 5 mice, Group B and C were further divided into two categories to assess acute and chronic effects of topical curcumin and UVB radiation. Each consisted of six subgroups of five mice. Subgroup 1; UVB exposure only (positive control) subgroup 2; acetone and UVB exposure, subgroup 3-6; topical curcumin application of 100nM, 1µM, 10µM, and 100µM concentrations, respectively. In Group C, there were two categories that received 3x/week UVB exposure for three weeks which effects were being observed at 24 hours and 10 days after the last exposure. The topical curcumin dose was 2mg/mL/cm applied 30 minutes prior to 343mJ/cm/day UVB irradiation. Skin biopsy was done one hour after the last UVB exposure for immunohistochemical and histopathology examinations.
RESULTS
Topical curcumin showed a limited yet robust protective effect against CPD and 8-OHdG expression in Group B, while in Group C all concentrations showed significant CPD and 8-OHdG inhibition after 10 days of UVB exposure. The 10µM and 100µM concentrations showed the best epidermal hyperplasia inhibition effect (p<0.05). No significant differences were found in terms in efficacy either in single nor daily application.
CONCLUSION
Topical curcumin can prevent the formation of the photoproducts CPD and 8-OHdG and epidermal hyperplasia in both acute and chronic exposure in UVB-induced mice.
PubMed: 36068854
DOI: 10.2147/CCID.S377055 -
Genetics Aug 2022Ultraviolet-induced DNA lesions impede DNA replication and transcription and are therefore a potential source of genome instability. Here, we performed serial transfer...
Ultraviolet-induced DNA lesions impede DNA replication and transcription and are therefore a potential source of genome instability. Here, we performed serial transfer experiments on nucleotide excision repair-deficient (rad14Δ) yeast cells in the presence of chronic low-dose ultraviolet irradiation, focusing on the mechanisms underlying adaptive responses to chronic low-dose ultraviolet irradiation. Our results show that the entire haploid rad14Δ population rapidly becomes diploid during chronic low-dose ultraviolet exposure, and the evolved diploid rad14Δ cells were more chronic low-dose ultraviolet-resistant than haploid cells. Strikingly, single-stranded DNA, but not pyrimidine dimer, accumulation is associated with diploid-dependent fitness in response to chronic low-dose ultraviolet stress, suggesting that efficient repair of single-stranded DNA tracts is beneficial for chronic low-dose ultraviolet tolerance. Consistent with this hypothesis, homologous recombination is essential for the rapid evolutionary adaptation of diploidy, and rad14Δ cells lacking Rad51 recombinase, a key player in homologous recombination, exhibited abnormal cell morphology characterized by multiple RPA-yellow fluorescent protein foci after chronic low-dose ultraviolet exposure. Furthermore, interhomolog recombination is increased in chronic low-dose ultraviolet-exposed rad14Δ diploids, which causes frequent loss of heterozygosity. Thus, our results highlight the importance of homologous recombination in the survival and genomic stability of cells with unrepaired lesions.
Topics: Diploidy; DNA Damage; DNA Repair; DNA, Single-Stranded; Homologous Recombination; Rad51 Recombinase; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ultraviolet Rays; Adaptation, Physiological
PubMed: 35946552
DOI: 10.1093/genetics/iyac115 -
Photochemistry and Photobiology Sep 2022The dominant DNA damage generated by UV exposure is the cyclobutane pyrimidine dimer (CPD), which alters skin cell physiology and induces cell death and mutation....
The dominant DNA damage generated by UV exposure is the cyclobutane pyrimidine dimer (CPD), which alters skin cell physiology and induces cell death and mutation. Genome-wide nucleotide-resolution analysis of CPDs in melanocytes and fibroblasts has identified "CPD hyperhotspots", pyrimidine-pyrimidine sites hundreds of fold more susceptible to the generation of CPDs than the genomic average. Identifying hyperhotspots in keratinocytes could enable measuring individual past UV exposure in small skin samples and predicting future skin cancer risk. We therefore exposed neonatal human epidermal keratinocytes to narrowband UVB and quantified CPDs using the adductSeq high-throughput DNA sequencing method. Keratinocytes contained thousands of CPD hyperhotspots, with a UVB-sensitivity up to 550 fold greater than the genomic average. As with melanocytes, the most sensitive sites were located in promoter regions at ETS-family transcription factor binding sequence motifs, near RNA processing genes. Moreover, they lay at sequence motifs bound to ETS1 in CpG islands. These genes were specifically upregulated in skin and the CPD hyperhotspots were mutated in a fraction of keratinocyte cancers. Crucially for their biological importance and practical application, CPD hyperhotspot locations and UV-sensitivity ranking demonstrated high reproducibility across experiments and across skin donors. CPD hyperhotspots are therefore sensitive indicators of UV exposure.
Topics: DNA Damage; Humans; Infant, Newborn; Keratinocytes; Pyrimidine Dimers; Reproducibility of Results; Transcription Factors; Ultraviolet Rays
PubMed: 35944237
DOI: 10.1111/php.13683 -
Biochimica Et Biophysica Acta.... Nov 2022Ultraviolet (UV) light irradiation generates pyrimidine dimers on DNA, such as cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts. Such dimers distort the...
Ultraviolet (UV) light irradiation generates pyrimidine dimers on DNA, such as cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts. Such dimers distort the high-order DNA structure and prevent transcription and replication. The nucleotide excision repair (NER) system contributes to resolving this type of DNA lesion. There are two pathways that recognize pyrimidine dimers. One acts on transcribed strands of DNA (transcription-coupled NER), and the other acts on the whole genome (global genome-NER; GG-NER). In the latter case, DNA damage-binding protein 2 (DDB2) senses pyrimidine dimers with several histone modification enzymes. We previously reported that histone acetyltransferase binding to ORC1 (HBO1) interacts with DDB2 and facilitates recruitment of the imitation switch chromatin remodeler at UV-irradiated sites via an unknown methyltransferase. Here, we found that the phosphorylated histone methyltransferase mixed lineage leukemia 1 (MLL1) was maintained at UV-irradiated sites in an HBO1-dependent manner. Furthermore, MLL1 catalyzed histone H3K4 methylation and recruited the chromatin remodeler bromodomain adjacent to zinc finger domain 1A (BAZ1A)/ATP-utilizing chromatin assembly and remodeling factor 1 (ACF1). Depletion of MLL1 suppressed BAZ1A accumulation at UV-irradiated sites and inhibited the removal of CPDs. These data indicate that the DDB2-HBO1-MLL1 axis is essential for the recruitment of BAZ1A to facilitate GG-NER.
Topics: Chromatin; Chromosomal Proteins, Non-Histone; DNA Damage; DNA Repair; Humans; Leukemia; Pyrimidine Dimers
PubMed: 35940372
DOI: 10.1016/j.bbamcr.2022.119332