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Genes, Chromosomes & Cancer Jan 2024Polyketide synthase (pks) island harboring Escherichia coli are, under the right circumstances, able to produce the genotoxin colibactin. Colibactin is a risk factor for...
Polyketide synthase (pks) island harboring Escherichia coli are, under the right circumstances, able to produce the genotoxin colibactin. Colibactin is a risk factor for the development of colorectal cancer and associated with mutational signatures SBS88 and ID18. This study explores colibactin-associated mutational signatures in biallelic NTHL1 and MUTYH patients. Targeted Next Generation Sequencing (NGS) was performed on colorectal adenomas and carcinomas of one biallelic NTHL and 12 biallelic MUTYH patients. Additional fecal metagenomics and genome sequencing followed by mutational signature analysis was conducted for the NTHL1 patient. Targeted NGS of the NTHL1 patient showed somatic APC variants fitting SBS88 which was confirmed using WGS. Furthermore, fecal metagenomics revealed pks genes. Also, in 1 out of 11 MUTYH patient a somatic variant was detected fitting SBS88. This report shows that colibactin may influence development of colorectal neoplasms in predisposed patients.
Topics: Humans; Adenomatous Polyposis Coli; Mutation; Colorectal Neoplasms; Deoxyribonuclease (Pyrimidine Dimer)
PubMed: 37795928
DOI: 10.1002/gcc.23208 -
Nucleic Acids Research Oct 2023UV radiation-induced DNA damages have adverse effects on genome integrity and cellular function. The most prevalent UV-induced DNA lesion is the cyclobutane pyrimidine...
UV radiation-induced DNA damages have adverse effects on genome integrity and cellular function. The most prevalent UV-induced DNA lesion is the cyclobutane pyrimidine dimer (CPD), which can cause skin disorders and cancers in humans. Rad4/XPC is a damage sensing protein that recognizes and repairs CPD lesions with high fidelity. However, the molecular mechanism of how Rad4/XPC interrogates CPD lesions remains elusive. Emerging viewpoints indicate that the association of Rad4/XPC with DNA, the insertion of a lesion-sensing β-hairpin of Rad4/XPC into the lesion site and the flipping of CPD's partner bases (5'-dA and 3'-dA) are essential for damage recognition. Characterizing these slow events is challenging due to their infrequent occurrence on molecular time scales. Herein, we have used enhanced sampling and molecular dynamics simulations to investigate the mechanism and energetics of lesion recognition by Rad4/XPC, considering multiple plausible pathways between the crystal structure of the Rad4-DNA complex and nine intermediate states. Our results shed light on the most likely sequence of events, their potential coupling and energetics. Upon association, Rad4 and DNA form an encounter complex in which CPD and its partner bases remain in the duplex and the BHD3 β-hairpin is yet to be inserted into the lesion site. Subsequently, sequential base flipping occurs, with the flipping of the 5'-dA base preceding that of the 3'-dA base, followed by the insertion of the BHD3 β-hairpin into the lesion site. The results presented here have significant implications for understanding the molecular basis of UV-related skin disorders and cancers and for paving the way for novel therapeutic strategies.
Topics: Humans; Pyrimidine Dimers; DNA Damage; DNA Repair; Saccharomyces cerevisiae Proteins; Protein Binding; DNA-Binding Proteins; DNA; Neoplasms; Ultraviolet Rays
PubMed: 37757853
DOI: 10.1093/nar/gkad730 -
Cureus Aug 2023Introduction Numerous studies have delved into the clinical efficacy of different topical treatments for actinic keratosis (AK). However, our understanding remains...
Exploring the Protective Efficacy of Topical Products for Actinic Keratosis Against Ultraviolet-Induced DNA and Protein Damage: An Experimental, Double-Blind Irradiation Study.
Introduction Numerous studies have delved into the clinical efficacy of different topical treatments for actinic keratosis (AK). However, our understanding remains limited regarding their capacity to prevent DNA and protein damage caused by ultraviolet radiation (UVR). Objectives The aim of this study was to analyze and compare the preventive capabilities of various AK-targeted products in countering DNA and protein alterations in human biopsies following exposure to experimental UVR. Methods Twelve healthy Caucasian volunteers (six men and six women) aged 18 years and above, with Fitzpatrick skin types II-III, participated in an experimental irradiation study. Six topical products, containing various ingredients (DNA repair enzymes, antioxidants, keratolytic agents, cyclooxygenase inhibitors, and/or sunscreens) were tested. The experimental sites were exposed to UVR at six times the minimal erythema dose for eight consecutive days. Each test product was applied 30 to 45 minutes before irradiation at a standard thickness of 2 mg/cm. A control site was treated with the vehicle alone, serving as a negative control. The study focused on cyclobutane pyrimidine dimers (CPDs) and protein carbonylation (PC) as molecular markers of UVR-induced DNA and protein damage, respectively. Results The efficacy of different AK-targeted topical products showed substantial variation when applied to normal skin before experimental exposure to UVR. While sunscreens, predictably, played a crucial role, additional ingredients (i.e., DNA repair enzymes and antioxidants) also acted as vital protective agents for both the cellular genome and proteome, shielding them against UVR-induced damage. Conclusion In topical products specifically designed for AK, the strategic integration of DNA repair enzymes and antioxidants, in addition to sunscreens, establishes a critical defense mechanism against the detrimental effects of UVR on cellular DNA and proteins.
PubMed: 37746407
DOI: 10.7759/cureus.44065 -
Journal of Hypertension Nov 2023Pharmacovigilance reports, associating hydrochlorothiazide (HCT) with skin cancer, resulted in a significant decrease of HCT prescriptions for hypertension and heart... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
Pharmacovigilance reports, associating hydrochlorothiazide (HCT) with skin cancer, resulted in a significant decrease of HCT prescriptions for hypertension and heart failure. Whether HCT exhibits phototoxic properties thereby causing skin cancer remains unknown. This study aimed to examine the photosensitizing, phototoxic and carcinogenic potential of HCT in a randomized, placebo-controlled, double-blind trial in vivo and also in vitro .
METHODS
The trial assigned 30 healthy, normotensive adult volunteers in a 2:1 ratio to either HCT 25 mg/day or placebo for 15 days. Photosensitivity of the skin with and without the effect of HCT treatment were assessed. Following whole-body ultraviolet A (UVA) and B (UVB, 311 nm) irradiation, phototoxic and carcinogenic reactions by measuring urinary excretion of pyrimidine dimers were evaluated. For the in-vitro studies, human keratinocytes (HaCaT) were incubated with HCT, irradiated with UVB, and analysed for markers of inflammation, apoptosis and carcinogenesis.
RESULTS
Skin photosensitivity following exposure to UVA and UVB remained unchanged from baseline to 15-day follow-up in both groups (UVA change HCT 0.0 J/cm 2 vs. placebo 0.0 J/cm 2 ; P = 0.99; UVB change HCT 0.0 J/cm 2 vs. placebo -0.2 J/cm 2 ; P = 0.06). Pyrimidine dimers were not detected in either group. In vitro , combination of HCT and UVB irradiation did not induce the expression of oxidative stress marker proteins, inflammatory proteins, apoptotic proteins or activation of oncoproteins.
CONCLUSION
HCT did not increase photosensitivity for UVA or UVB in healthy volunteers compared with placebo, and was not associated with phototoxic or carcinogenic reactions. In vitro , HCT was also not associated with phototoxicity or carcinogenesis (NCT04654312).
Topics: Humans; Hydrochlorothiazide; Male; Adult; Double-Blind Method; Female; Ultraviolet Rays; Skin Neoplasms; Healthy Volunteers; Middle Aged; Keratinocytes; Antihypertensive Agents; Skin; Dermatitis, Phototoxic; Photosensitizing Agents
PubMed: 37702559
DOI: 10.1097/HJH.0000000000003558 -
Astrobiology Sep 2023Organic matter is actively searched on Mars with current and future space missions as it is a key to detecting potential biosignatures. Given the current harsh...
Organic matter is actively searched on Mars with current and future space missions as it is a key to detecting potential biosignatures. Given the current harsh environmental conditions at the surface of Mars, many organic compounds might not be preserved over a long period as they are exposed to energetic radiation such as ultraviolet light, which is not filtered above 190 nm by the martian atmosphere. Moreover, the presence of strong oxidizing species in the regolith, such as perchlorate salts, might enhance the photodegradation of organic compounds of astrobiological interest. Because current space instruments analyze samples collected in the upper surface layer, it is necessary to investigate the stability of organic matter at the surface of Mars. Previous experimental studies have shown that uracil, a molecule relevant to astrobiology, is quickly photolyzed when exposed to UV radiation under the temperature and pressure conditions of the martian surface with an experimental quantum efficiency of photodecomposition (φ) of 0.30 ± 0.26 molecule·photon. Moreover, the photolysis of uracil leads to the formation of more stable photoproducts that were identified as uracil dimers. The present work aims to characterize the additional effect of calcium perchlorate detected on Mars on the degradation of uracil. Results show that the presence of calcium perchlorate enhances the photodecomposition of uracil with φ = 12.3 ± 8.3 molecule·photon. Although some of the photoproducts formed during these experiments are common to those formed from pure uracil only, the Fourier transformation infrared (FTIR) detection of previously unseen chemical functions such as alkyne C ≡ C or nitrile C ≡ N has shown that additional chemical species are formed in the presence of calcium perchlorate in the irradiated sample. This implies that the effect of calcium perchlorate on the photolysis of uracil is not only kinetic but also related to the nature of the photoproducts formed.
Topics: Calcium; Fluorides; Ultraviolet Rays; Perchlorates; Temperature; Extraterrestrial Environment; Mars
PubMed: 37672714
DOI: 10.1089/ast.2022.0137 -
Food & Function Sep 2023ζ-Carotene is a key intermediate in the carotenoid pathway, but owing to its low content and difficulties in isolation, its application is restricted. In this study,...
ζ-Carotene is a key intermediate in the carotenoid pathway, but owing to its low content and difficulties in isolation, its application is restricted. In this study, three genes (, , and ) in the carotenoid pathway of Antarctic moss were identified, recombined, and expressed in () BL21(DE3). The expression product was identified as one of the ζ-carotenes by UV absorbance spectrum, thin layer chromatography (TLC), and super-high-performance liquid chromatography-mass spectrum (UPLC-MS), and was called a ζ-carotene-like compound (CLC). Excessive exposure to ultraviolet B (UVB) irradiation is one of the main risk factors for skin photodamage. The purpose of this study was to investigate the preventive and therapeutic effects of CLC on UVB-induced skin photodamage in mice. In this paper, through histological examinations (hematoxylin-eosin, HE; Masson and TdT-mediated dUTP Nick-End Labeling, Tunel), biochemical index detection (reactive oxygen species, ROS; inflammatory factors; cyclobutyl pyrimidine dimers, CPDs and hyaluronic acid, HA), quantitative real time polymerase chain reaction (qRT-PCR), immunohistochemistry and intestinal content flora, , it is concluded that CLC has the potential to enhance skin antioxidant capacity by activating the nuclear transcription factor/antioxidant reaction element (Nrf2/ARE) pathway and also reduce skin inflammation and aging by inhibiting the mitogen-activated protein kinase (MAPK) pathway. Moreover, the regulation of intestinal flora may potentially mitigate skin damage induced by UVB radiation. This research not only developed a green and sustainable platform for the efficient synthesis of CLC but also laid a foundation for its application in functional food and medicine for skin resistance against UVB damage.
Topics: Animals; Mice; zeta Carotene; Antioxidants; Chromatography, Liquid; Escherichia coli; Gastrointestinal Microbiome; Tandem Mass Spectrometry; Inflammation; Carotenoids
PubMed: 37606633
DOI: 10.1039/d3fo02502k -
Environmental and Molecular Mutagenesis Apr 2024Exposure to ultraviolet (UV) light is the primary etiological agent for skin cancers because UV damages cellular DNA. The most frequent form of UV damage is the...
Exposure to ultraviolet (UV) light is the primary etiological agent for skin cancers because UV damages cellular DNA. The most frequent form of UV damage is the cyclobutane pyrimidine dimer (CPD), which consists of covalent linkages between neighboring pyrimidine bases in DNA. In human cells, the 5' position of cytosine bases in CG dinucleotides is frequently methylated, and methylated cytosines in the TP53 tumor suppressor are often sites of mutation hotspots in skin cancers. It has been argued that this is because cytosine methylation promotes UV-induced CPD formation; however, the effects of cytosine methylation on CPD formation are controversial, with conflicting results from previous studies. Here, we use a genome-wide method known as CPD-seq to map UVB- and UVC-induced CPDs across the yeast genome in the presence or absence in vitro methylation by the CpG methyltransferase M.SssI. Our data indicate that cytosine methylation increases UVB-induced CPD formation nearly 2-fold relative to unmethylated DNA, but the magnitude of induction depends on the flanking sequence context. Sequence contexts with a 5' guanine base (e.g., GCCG and GTCG) show the strongest induction due to cytosine methylation, potentially because these sequence contexts are less efficient at forming CPD lesions in the absence of methylation. We show that cytosine methylation also modulates UVC-induced CPD formation, albeit to a lesser extent than UVB. These findings can potentially reconcile previous studies, and define the impact of cytosine methylation on UV damage across a eukaryotic genome.
Topics: Humans; Pyrimidine Dimers; Base Sequence; DNA Damage; DNA Methylation; Cytosine; DNA; Ultraviolet Rays; Skin Neoplasms
PubMed: 37554110
DOI: 10.1002/em.22569 -
Experimental Dermatology Sep 2023Far-UVC radiation sources of wavelengths 222 nm and 233 nm represent an interesting potential alternative for the antiseptic treatment of the skin due to their high...
Far-UVC radiation sources of wavelengths 222 nm and 233 nm represent an interesting potential alternative for the antiseptic treatment of the skin due to their high skin compatibility. Nevertheless, no studies on far-UVC-induced DNA damage in different skin types have been published to date, which this study aims for. After irradiating the skin with far-UVC of the wavelengths 222 and 233 nm as well as broadband UVB, the tissue was screened for cyclobutane pyrimidine dimer-positive (CPD ) cells using immunohistochemistry. The epidermal DNA damage was lower in dark skin types than in fair skin types after irradiation at 233 nm. Contrary to this, irradiation at 222 nm caused no skin type-dependent differences, which can be attributed to the decreased penetration depth of radiation. UVB showed the relatively strongest differences between light and dark skin types when using a suberythemal dose of 3 mJ/cm . As melanin is known for its photoprotective effect, we evaluated the ratio of melanin content in the stratum basale and stratum granulosum in samples of different skin types using two-photon excited fluorescence lifetime imaging (TPE-FLIM) finding a higher ratio up to skin type IV-V. As far-UVC is known to penetrate only into the upper layers of the viable skin, the aforementioned melanin ratio could explain the less pronounced differences between skin types after irradiation with far-UVC compared to UVB.
Topics: Melanins; DNA Damage; Pyrimidine Dimers; Epidermis; Ultraviolet Rays
PubMed: 37545424
DOI: 10.1111/exd.14902 -
Environmental and Molecular Mutagenesis Apr 2024DNA damage occurs throughout life from a variety of sources, and it is imperative to repair damage in a timely manner to maintain genome stability. Thus, DNA repair... (Review)
Review
DNA damage occurs throughout life from a variety of sources, and it is imperative to repair damage in a timely manner to maintain genome stability. Thus, DNA repair mechanisms are a fundamental part of life. Nucleotide excision repair (NER) plays an important role in the removal of bulky DNA adducts, such as cyclobutane pyrimidine dimers from ultraviolet light or DNA crosslinking damage from platinum-based chemotherapeutics, such as cisplatin. A main component for the NER pathway is transcription factor IIH (TFIIH), a multifunctional, 10-subunit protein complex with crucial roles in both transcription and NER. In transcription, TFIIH is a component of the pre-initiation complex and is important for promoter opening and the phosphorylation of RNA Polymerase II (RNA Pol II). During repair, TFIIH is important for DNA unwinding, recruitment of downstream repair factors, and verification of the bulky lesion. Several different disease states can arise from mutations within subunits of the TFIIH complex. Most strikingly are xeroderma pigmentosum (XP), XP combined with Cockayne syndrome (CS), and trichothiodystrophy (TTD). Here, we summarize the recruitment and functions of TFIIH in the two NER subpathways, global genomic (GG-NER) and transcription-coupled NER (TC-NER). We will also discuss how TFIIH's roles in the two subpathways lead to different genetic disorders.
Topics: Humans; DNA; DNA Damage; DNA Repair; Excision Repair; Transcription Factor TFIIH; Transcription, Genetic; Xeroderma Pigmentosum
PubMed: 37545038
DOI: 10.1002/em.22568