Persistence and Tolerance of DNA Damage Induced by Chronic UVB Irradiation of the Human Genome

Bérubé, Roxanne; Desgarnier, Marie-Catherine Drigeard; Douki, Thierry; Lechasseur, Ariane; Rochette, Patrick J.

doi:10.1016/j.jid.2017.08.044

Cited by 24 publications

(18 citation statements)

References 39 publications

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“…If CPDs accumulated in hyperhotspots, these regions could serve as objective sentinels of prior exposure, quantifiable in small skin samples. CPDs are known to persist unrepaired for at least 1 wk in telomeres and heterochromatin of proliferating mammalian cells (8,72) and for over 1 mo in epidermal stem cells (73). The present study found that, indeed, class 2 hyperhotspot sites had accumulated CPDs in the days or weeks before the experiment began, presumably reflecting internal CPD production by chemiexcitation (31).…”

Section: Discussionmentioning

confidence: 99%

Genomic sites hypersensitive to ultraviolet radiation

Premi

Han

Mehta³

et al. 2019

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

113

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If the genome contains outlier sequences extraordinarily sensitive to environmental agents, these would be sentinels for monitoring personal carcinogen exposure and might drive direct changes in cell physiology rather than acting through rare mutations. New methods, adductSeq and freqSeq, provided statistical resolution to quantify rare lesions at single-base resolution across the genome. Primary human melanocytes, but not fibroblasts, carried spontaneous apurinic sites and TG sequence lesions more frequent than ultraviolet (UV)-induced cyclobutane pyrimidine dimers (CPDs). UV exposure revealed hyperhotspots acquiring CPDs up to 170-fold more frequently than the genomic average; these sites were more prevalent in melanocytes. Hyperhotspots were disproportionately located near genes, particularly for RNA-binding proteins, with the most-recurrent hyperhotspots at a fixed position within 2 motifs. One motif occurs at ETS family transcription factor binding sites, known to be UV targets and now shown to be among the most sensitive in the genome, and at sites of mTOR/5′ terminal oligopyrimidine-tract translation regulation. The second occurs at A2–15TTCTY, which developed “dark CPDs” long after UV exposure, repaired CPDs slowly, and had accumulated CPDs prior to the experiment. Motif locations active as hyperhotspots differed between cell types. Melanocyte CPD hyperhotspots aligned precisely with recurrent UV signature mutations in individual gene promoters of melanomas and with known cancer drivers. At sunburn levels of UV exposure, every cell would have a hyperhotspot CPD in each of the ∼20 targeted cell pathways, letting hyperhotspots act as epigenetic marks that create phenome instability; high prevalence favors cooccurring mutations, which would allow tumor evolution to use weak drivers.

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Section: Discussionmentioning

confidence: 99%

Genomic sites hypersensitive to ultraviolet radiation

Premi

Han

Mehta³

et al. 2019

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

113

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“…Our previous experiments showed that UVB caused S-phase cell cycle arrest to prevent further DNA damage and minimize the likelihood of introducing gene mutations in daughter cells. An early mechanism involved in CPD repair is activation of the DNA damage checkpoint that activates cell cycle delay to allow efficient repair [6]. Nucleotide excision repair (NER) is an important repair system that can remove UV-induced photolesions in placental mammals [34].…”

Section: Discussionmentioning

confidence: 99%

“…Repetitive exposure to UVB increases the cellular reactive oxygen species (ROS) level, resulting in strand breaks and hydroxylation of DNA bases [5]. UVB can induce cell cycle arrest and mutagenic DNA damage, such as formation of cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproduct [6, 7]. These changes have detrimental effects that include carcinogenesis, cell senescence, and other skin pathologies [8].…”

Section: Introductionmentioning

confidence: 99%

Rapamycin Protects Skin Fibroblasts from Ultraviolet B-Induced Photoaging by Suppressing the Production of Reactive Oxygen Species

Qin

Ren

Jia

et al. 2018

Cell Physiol Biochem

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Background/Aims: Ultraviolet B (UVB) irradiation alters multiple molecular pathways in the skin, thereby inducing skin photoaging. Murine dermal fibroblasts (MDFs) were subjected to a series of 4 sub-cytotoxic UVB doses (120 mJ/cm²), resulting in changes in cell shape, DNA damage, cell cycle arrest, extracellular matrix variations, reactive oxygen species (ROS) generation, and alterations in major intracellular antioxidant and cellular autophagy levels. Rapamycin (RAPA) is a new macrolide immunosuppressive agent that is primarily used in oncology, cardiology, and transplantation medicine and has been found to extend the lifespan of genetically heterogeneous mice. Several studies have shown that RAPA may have anti-aging effects in cells and organisms. Thus, in this study, we explored the effects and mechanisms of RAPA against the photoaging process using a well-established cellular photoaging model. Methods: We developed a stress-induced premature senescence (SIPS) model through repeated exposure of MDFs to ultraviolet B (UVB) irradiation. The cells were cultured in the absence or presence of RAPA for 48 h. Senescent phenotypes were assessed by examining cell viability, cell morphology, senescence-associated β-galactosidase (SA-β-gal) expression, cell cycle progression, intracellular ROS production, matrix metalloproteinase (MMP) synthesis and degradation, extracellular matrix (ECM) component protein expression, alterations in major intracellular antioxidant levels, and the cellular autophagy level. Results: Compared with the UVB group, pretreatment with RAPA (5 µM) significantly decreased the staining intensity and percentage of SA-β-gal-positive cells and preserved the elongated cell shape. Moreover, cells pretreated with RAPA showed inhibition of the reduction in the type I collagen content by blocking the UVB-induced upregulation of MMP expression. RAPA also decreased photoaging cell cycle arrest and downregulated p53 and p21 expression. RAPA application significantly attenuated irradiation-induced ROS release by modulating intracellular antioxidants and increasing the autophagy level. Conclusions: Our study demonstrated that RAPA elicited oxidative damage in vitro by reducing ROS accumulation in photoaged fibroblasts. The anti-aging effect can be attributed to the maintenance of normal antioxidant and cellular autophagy levels. However, determination of the definitive mechanism requires further study.

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“…UVB (280–315 nm) irradiation causes direct DNA and RNA damage by inducing covalent bond formation between adjacent pyrimidines, leading to the generation of mutagenic photoproducts, such as cyclopyrimidine dimers and pyrimidine-pyrimidine (6-4) adducts [ 40 , 41 ]. Additionally, UVA (315–400 nm) causes indirect DNA damage through a photo-oxidative stress-mediated mechanism, resulting in the formation of reactive oxygen species, which interact with lipids, proteins, and DNA to generate intermediates that combine with DNA to form harmful adducts [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Are FDA-Approved Sunscreen Components Effective in Preventing Solar UV-Induced Skin Cancer?

Bode

Roh

2020

Cells

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Solar ultraviolet (SUV) exposure is a major risk factor in the etiology of cutaneous squamous cell carcinoma (cSCC). People commonly use sunscreens to prevent SUV-induced skin damage and cancer. Nonetheless, the prevalence of cSCC continues to increase every year, suggesting that commercially available sunscreens might not be used appropriately or are not completely effective. In the current study, a solar simulated light (SSL)-induced cSCC mouse model was used to investigate the efficacy of eight commonly used FDA-approved sunscreen components against skin carcinogenesis. First, we tested FDA-approved sunscreen components for their ability to block UVA or UVB irradiation by using VITRO-SKIN (a model that mimics human skin properties), and then the efficacy of FDA-approved sunscreen components was investigated in an SSL-induced cSCC mouse model. Our results identified which FDA-approved sunscreen components or combinations are effective in preventing cSCC development. Not surprisingly, the results indicated that sunscreen combinations that block both UVA and UVB significantly suppressed the formation of cutaneous papillomas and cSCC development and decreased the activation of oncoproteins and the expression of COX-2, keratin 17, and EGFR in SSL-exposed SKH-1 (Crl:SKH1-Hrhr) hairless mouse skin. Notably, several sunscreen components that were individually purported to block both UVA and UVB were ineffective alone. At least one component had toxic effects that led to a high mortality rate in mice exposed to SSL. Our findings provide new insights into the development of the best sunscreen to prevent chronic SUV-induced cSCC development.

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Persistence and Tolerance of DNA Damage Induced by Chronic UVB Irradiation of the Human Genome

Cited by 24 publications

References 39 publications

Genomic sites hypersensitive to ultraviolet radiation

Genomic sites hypersensitive to ultraviolet radiation

Rapamycin Protects Skin Fibroblasts from Ultraviolet B-Induced Photoaging by Suppressing the Production of Reactive Oxygen Species

Are FDA-Approved Sunscreen Components Effective in Preventing Solar UV-Induced Skin Cancer?

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