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Chemico-biological Interactions Jan 2024Cyclobutane pyrimidine dimer (CPD) and (6-4)photoproduct (6-4 PP) are two major types of UV-induced DNA lesion and 6-4 PP is more mutagenic than CPD. Activated by...
Thallium(I) induces a prolonged inhibition of (6-4)photoproduct binding and UV damage excision repair activities in zebrafish (Danio rerio) embryos via protein inactivation.
Cyclobutane pyrimidine dimer (CPD) and (6-4)photoproduct (6-4 PP) are two major types of UV-induced DNA lesion and 6-4 PP is more mutagenic than CPD. Activated by lesion detection, nucleotide excision repair (NER) eliminates CPDs and 6-4 PPs. Thallium (Tl) is a toxic metal existing primarily as Tl in the aquatic environment. Ingestion of Tl-contaminated foods and water is a major route of human poisoning. As Tl may inhibit enzyme activities via binding to sulfhydryl groups, this study explored if Tl could intensify UV mutagenicity by inactivating NER-linked damage recognition factors using zebrafish (Danio rerio) embryo as a model system. Incubation of Tl (as thallium nitrate) at 0.1-0.4 μg/mL with zebrafish extracts for 20 min caused a concentration-dependent inhibition of 6-4 PP binding activities as shown by a photolesion-specific band shift assay, while CPD binding activities were insensitive to Tl. The ability of Tl to suppress 6-4 PP detection was stronger than that of Hg. Exposure of zebrafish embryos at 1 h post fertilization (hpf) to Tl at 0.4-1 μg/mL for 9 or 71 h also specifically inhibited 6-4 PP detection, indicating that Tl induced a prolonged inhibition of 6-4 PP sensing ability primarily via its direct interaction with damage recognition molecules. Tl-mediated inhibition of 6-4 PP binding in embryos at distinct stages resulted in a suppression of NER capacity monitored by a transcription-based DNA repair assay. Our results revealed the potential of Tl to enhance UV mutagenicity by disturbing the removal of 6-4 PP through repressing the lesion detection step of NER.
Topics: Animals; Humans; Zebrafish; Excision Repair; Thallium; DNA Repair; DNA Damage; Pyrimidine Dimers; Ultraviolet Rays
PubMed: 38104746
DOI: 10.1016/j.cbi.2023.110837 -
Scientific Reports Nov 2023In search of novel breast cancer (BC) risk variants, we performed a whole-exome sequencing and variant analysis of 69 Finnish BC patients as well as analysed...
In search of novel breast cancer (BC) risk variants, we performed a whole-exome sequencing and variant analysis of 69 Finnish BC patients as well as analysed loss-of-function variants identified in DNA repair genes in the Finns from the Genome Aggregation Database. Additionally, we carried out a validation study of SERPINA3 c.918-1G>C, recently suggested for BC predisposition. We estimated the frequencies of 41 rare candidate variants in 38 genes by genotyping them in 2482-4101 BC patients and in 1273-3985 controls. We further evaluated all coding variants in the candidate genes in a dataset of 18,786 BC patients and 182,927 controls from FinnGen. None of the variants associated significantly with cancer risk in the primary BC series; however, in the FinnGen data, NTHL1 c.244C>T p.(Gln82Ter) associated with BC with a high risk for homozygous (OR = 44.7 [95% CI 6.90-290], P = 6.7 × 10) and a low risk for heterozygous women (OR = 1.39 [1.18-1.64], P = 7.8 × 10). Furthermore, the results suggested a high risk of colorectal, urinary tract, and basal-cell skin cancer for homozygous individuals, supporting NTHL1 as a recessive multi-tumour susceptibility gene. No significant association with BC risk was detected for SERPINA3 or any other evaluated gene.
Topics: Humans; Female; Genetic Predisposition to Disease; Breast Neoplasms; Heterozygote; Breast; Finland; Deoxyribonuclease (Pyrimidine Dimer)
PubMed: 38036545
DOI: 10.1038/s41598-023-47441-w -
Science (New York, N.Y.) Dec 2023Dissection of multistep catalysis by a photoenzyme could inspire green chemistry applications.
Dissection of multistep catalysis by a photoenzyme could inspire green chemistry applications.
Topics: Catalysis; DNA Repair; Deoxyribodipyrimidine Photo-Lyase; Pyrimidine Dimers; DNA Damage; DNA; Ultraviolet Rays
PubMed: 38033077
DOI: 10.1126/science.adl3002 -
Science (New York, N.Y.) Dec 2023Photolyases, a ubiquitous class of flavoproteins, use blue light to repair DNA photolesions. In this work, we determined the structural mechanism of the...
Photolyases, a ubiquitous class of flavoproteins, use blue light to repair DNA photolesions. In this work, we determined the structural mechanism of the photolyase-catalyzed repair of a cyclobutane pyrimidine dimer (CPD) lesion using time-resolved serial femtosecond crystallography (TR-SFX). We obtained 18 snapshots that show time-dependent changes in four reaction loci. We used these results to create a movie that depicts the repair of CPD lesions in the picosecond-to-nanosecond range, followed by the recovery of the enzymatic moieties involved in catalysis, completing the formation of the fully reduced enzyme-product complex at 500 nanoseconds. Finally, back-flip intermediates of the thymine bases to reanneal the DNA were captured at 25 to 200 microseconds. Our data cover the complete molecular mechanism of a photolyase and, importantly, its chemistry and enzymatic catalysis at work across a wide timescale and at atomic resolution.
Topics: Archaeal Proteins; Catalysis; Crystallography; Deoxyribodipyrimidine Photo-Lyase; DNA; DNA Repair; Methanosarcina; Protein Conformation; Pyrimidine Dimers; Ultraviolet Rays
PubMed: 38033054
DOI: 10.1126/science.add7795 -
Journal of Biophotonics Feb 2024Photobiomodulation (PBM) can be used to treat a range of conditions in dermatology. PBM refers to the changes induced by red (RL, 620-700 nm) and near-infrared (NIR,...
Photobiomodulation (PBM) can be used to treat a range of conditions in dermatology. PBM refers to the changes induced by red (RL, 620-700 nm) and near-infrared (NIR, 700-1440 nm) light. Light radiation-induced DNA damage is a major contributor to aging and skin cancer. It is crucial to study the effects of PBM on DNA to ensure safety. Our lab previously demonstrated that RL (633 ± 6 nm) did not result in human dermal fibroblasts (HDFs) DNA damage. This study employed similar methods to investigate NIR effects. Commercially available LED-NIR (830 ± 5 nm) panels (66, 132, and 264 J/cm ) did not result in DNA damage measured by cyclobutane pyrimidine dimers and pyrimidine-6,4-pyrimidone photoproducts in HDFs compared to temperature-matched controls immediately, 3 h, and 24 h following irradiation and compared to positive and negative controls. This demonstrates that LED-NIR does not damage DNA in HDFs in vitro.
Topics: Humans; DNA Damage; Skin; Infrared Rays; Fibroblasts; DNA
PubMed: 38019097
DOI: 10.1002/jbio.202300388 -
Photochemistry and Photobiology 2024Prolonged ultraviolet exposure results in the formation of cyclobutane pyrimidine dimers (CPDs) in RNA. Consequently, prebiotic photolesion repair mechanisms should have...
Prolonged ultraviolet exposure results in the formation of cyclobutane pyrimidine dimers (CPDs) in RNA. Consequently, prebiotic photolesion repair mechanisms should have played an important role in the maintenance of the structural integrity of primitive nucleic acids. 2,6-Diaminopurine is a prebiotic nucleobase that repairs CPDs with high efficiency when incorporated into polymers. We investigate the electronic deactivation pathways of 2,6-diaminopurine-2'-deoxyribose and 9-methyl-2,6-diaminopurine in acetonitrile and aqueous solution to shed light on the photophysical and excited state properties of the 2,6-diaminopurine chromophore. Evidence is presented that both are photostable compounds exhibiting similar deactivation mechanisms upon the population of the S (ππ* L ) state at 290 nm. The mechanism involves deactivation through the C2- and C6-reaction coordinates and >99% of the excited state population decays through nonradiative pathways involving two conical intersections with the ground state. The radiative and nonradiative lifetimes are longer in aqueous solution compared to acetonitrile. While τ is similar in both derivatives, τ is ca. 1.5-fold longer in 2,6-diaminopurine-2'-deoxyribose due to a more efficient trapping in the S (ππ* L ) minimum. Therefore, 2,6-diaminopurine could have accumulated in significant quantities during prebiotic times to be incorporated into non-canonical RNA and play a significant role in its photoprotection.
Topics: Deoxyribose; 2-Aminopurine; Water; RNA; Acetonitriles
PubMed: 38018292
DOI: 10.1111/php.13887 -
Bioelectrochemistry (Amsterdam,... Apr 2024Low-energy electron beams (LEEB) are a safe and practical sterilization solution for in-line industrial applications, such as sterilizing medical products. However,...
Low-energy electron beams (LEEB) are a safe and practical sterilization solution for in-line industrial applications, such as sterilizing medical products. However, their low dose rate induces product degradation, and the limited maximal energy prohibits high-throughput applications. To address this, we developed a low-energy 'pulsed' electron beam generator (LEPEB) and evaluated its efficacy and mechanism of action. Bacillus pumilus vegetative cells and spores were irradiated with a 250 keV LEPEB system at a 100 Hz pulse repetition frequency and a pulse duration of only 10 ns. This produced highly efficient bacterial inactivation at a rate of >6 log, the level required for sterilization in industrial applications, with only two pulses for vegetative bacteria (20 ms) and eight pulses for spores (80 ms). LEPEB induced no morphological or structural defects, but decreased cell wall hydrophobicity in vegetative cells, which may inhibit biofilm formation. Single- and double-strand DNA breaks and pyrimidine dimer formation were also observed, likely causing cell death. Together, the unique combination of high dose rate and nanosecond delivery of LEPEB enable effective and high-throughput bacterial eradication for direct integration into production lines in a wide range of industrial applications.
Topics: Electrons; Bacteria; Sterilization
PubMed: 37995503
DOI: 10.1016/j.bioelechem.2023.108593 -
BioRxiv : the Preprint Server For... Nov 2023UV light is a potent mutagen that induces bulky DNA damage in the form of cyclobutane pyrimidine dimers (CPDs). In eukaryotic cells, photodamage and other bulky lesions...
UV light is a potent mutagen that induces bulky DNA damage in the form of cyclobutane pyrimidine dimers (CPDs). In eukaryotic cells, photodamage and other bulky lesions occurring in nuclear genomes (nucDNAs) can be repaired through nucleotide excision repair (NER), where dual incisions on both sides of a damaged site precede the removal of a single-stranded oligonucleotide containing the damage. Mitochondrial genomes (mtDNAs) are also susceptible to damage from UV light, but current views hold that the only way to eliminate bulky DNA damage in mtDNAs is through mtDNA degradation. Damage-containing oligonucleotides excised during NER can be captured with anti-damage antibodies and sequenced (XR-seq) to produce high resolution maps of active repair locations following UV exposure. We analyzed previously published datasets from , and to identify reads originating from the mtDNA (and plastid genome in ). In and , the mtDNA-mapping reads have unique length distributions compared to the nuclear-mapping reads. The dominant fragment size was 26 nt in and 28 nt in with distinct secondary peaks occurring in 2-nt () or 4-nt () intervals. These reads also show a nonrandom distribution of di-pyrimidines (the substrate for CPD formation) with TT enrichment at positions 7-8 of the reads. Therefore, UV damage to mtDNA appears to result in production of DNA fragments of characteristic lengths and positions relative to the damaged location. We hypothesize that these fragments may reflect the outcome of a previously uncharacterized mechanism of NER-like repair in mitochondria or a programmed mtDNA degradation pathway.
PubMed: 37986892
DOI: 10.1101/2023.11.07.566130 -
Mutation Research 2024Human xeroderma pigmentosum variant (XP-V) patients are mutated in the POLH gene, responsible for encoding the translesion synthesis (TLS) DNA polymerase eta (Pol eta).... (Review)
Review
Human xeroderma pigmentosum variant (XP-V) patients are mutated in the POLH gene, responsible for encoding the translesion synthesis (TLS) DNA polymerase eta (Pol eta). These patients suffer from a high frequency of skin tumors. Despite several decades of research, studies on Pol eta still offer an intriguing paradox: How does this error-prone polymerase suppress mutations? This review examines recent evidence suggesting that cyclobutane pyrimidine dimers (CPDs) are instructional for Pol eta. Consequently, it can accurately replicate these lesions, and the mutagenic effects induced by UV radiation stem from the deamination of C-containing CPDs. In this model, the deamination of C (forming a U) within CPDs leads to the correct insertion of an A opposite to the deaminated C (or U)-containing dimers. This intricate process results in C>T transitions, which represent the most prevalent mutations detected in skin cancers. Finally, the delayed replication in XP-V cells amplifies the process of C-deamination in CPDs and increases the burden of C>T mutations prevalent in XP-V tumors through the activity of backup TLS polymerases.
Topics: DNA-Directed DNA Polymerase; Humans; Pyrimidine Dimers; Ultraviolet Rays; Mutagenesis; Skin Neoplasms; Xeroderma Pigmentosum; DNA Repair; DNA Replication; Mutation; DNA Damage
PubMed: 37984186
DOI: 10.1016/j.mrfmmm.2023.111840 -
Journal of Cosmetic Dermatology Mar 2024UV skin exposure is an important matter of public health, as the worldwide rising prevalence of skin cancers indicates. However, a wide majority of commercially...
BACKGROUND
UV skin exposure is an important matter of public health, as the worldwide rising prevalence of skin cancers indicates. However, a wide majority of commercially available sunscreens are responsible for ocean ecosystem damages such as coral reef degradation and phytoplankton mortality.
AIMS
To answer the urge for new eco-friendly UV filters, we studied the use of lecithin-based multilamellar liposomes (MLLs) of controlled size and elasticity as a bio-sourced and biodegradable alternative to classic sunscreens. These parameters control allows different skin layers targeting.
METHODS
The performance of two different MLLs compositions and a commercially available SPF50+ water-resistant liposomal sunscreen was compared on skin explants. SC-MLLs target the stratum corneum and Epi-MLLs the whole epidermis. Preparations were applied prior to skin irradiation. Their efficiencies were evaluated histologically (hematoxylin and eosin staining plus cyclobutane pyrimidine dimer [CPD] immunostaining) and by skin barrier quality assessment (trans-epithelial electrical resistance). Adhesiveness to the skin was also investigated.
RESULTS
Altogether, ex vivo results indicate MLLs offer a solar protection as effective as a SPF50+ water-resistant liposomal sunscreen but with a better skin adhesiveness and an improved skin barrier function.
CONCLUSION
Lecithin-based MLLs of controlled physicochemical parameters can be used as a new eco-friendly and water-resistant agent for solar protection. The stratum corneum targeted action of SC-MLLs appears to be more interesting, as SC-MLLs exhibit an overall better performance than Epi-MLLs at a lower cost. The skin barrier improvement showcased could be of interest to people suffering from dry skin or skin barrier impairment related disease.
Topics: Humans; Sunscreening Agents; Liposomes; Lecithins; Water; Ecosystem; Ultraviolet Rays; Skin
PubMed: 37947116
DOI: 10.1111/jocd.16072