-
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 -
Journal of the European Academy of... Jul 2024This review aimed at summarizing some of the key points that were discussed during the photoprotection session at the International Forum of Dermatology in 2022. This... (Review)
Review
This review aimed at summarizing some of the key points that were discussed during the photoprotection session at the International Forum of Dermatology in 2022. This international conference was designed to address prominent topics of clinical dermatology in a holistic way, allowing to articulate multiple viewpoints. Therefore, this review does not claim to be exhaustive, but is instead intended to give an overview of recent developments and ongoing controversies in the field of photoprotection. Cumulative ultraviolet radiation (UVR) exposure is the major aetiological factor in the development of photoageing, photoimunosuppression and photocarcinogenesis. UVA (320-400 nm) penetrates into the dermis and damages DNA and other intracellular and acellular targets primarily by generating reactive oxygen species (ROS). It is the major contributor to photoageing, characterized by fine and coarse wrinkles, dyspigmentation and loss of elasticity. UVB (290-320 nm) is responsible for sunburns through direct damage to DNA by the formation of 6-4 cyclobutane pyrimidine dimers (CPDs) and pyrimidine 6-4 pyrimidone photoproducts. Both UVA and UVB exposure increase the risk of basal cell carcinoma, squamous cell carcinoma and melanoma. In recent years, visible light (VL; 400-700 nm) has also been implicated in the exacerbation of conditions aggravated by sun exposure such as hyperpigmentation and melasma. Photoprotection is a critical health strategy to reduce the deleterious effects of UVR and VL. Comprehensive photoprotection strategies include staying in the shade when outdoors, wearing photoprotective clothing including a wide-brimmed hat, and sunglasses, and the use of sunscreen. Due to the absorption of UV filters, the safety of sunscreens has been questioned. Newer sunscreens are becoming available with filters with absorption even beyond the UV spectrum, offering enhanced protection compared with older products. Prevention of photocarcinogenesis, sun-induced or sunlight-exacerbated hyperpigmentary conditions and drug-induced photosensitivity is an important reason for adopting comprehensive photoprotection strategies.
Topics: Humans; Sunscreening Agents; Ultraviolet Rays; Skin Aging; Skin Neoplasms; Sunburn
PubMed: 38924160
DOI: 10.1111/jdv.19677 -
Current Issues in Molecular Biology Feb 2024Ultraviolet (UV) radiation plays a crucial role in the development of melanoma and non-melanoma skin cancers. The types of UV radiation are differentiated by wavelength:... (Review)
Review
Ultraviolet (UV) radiation plays a crucial role in the development of melanoma and non-melanoma skin cancers. The types of UV radiation are differentiated by wavelength: UVA (315 to 400 nm), UVB (280 to 320 nm), and UVC (100 to 280 nm). UV radiation can cause direct DNA damage in the forms of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). In addition, UV radiation can also cause DNA damage indirectly through photosensitization reactions caused by reactive oxygen species (ROS), which manifest as 8-hydroxy-2'-deoxyguanine (8-OHdG). Both direct and indirect DNA damage can lead to mutations in genes that promote the development of skin cancers. The development of melanoma is largely influenced by the signaling of the melanocortin one receptor (MC1R), which plays an essential role in the synthesis of melanin in the skin. UV-induced mutations in the BRAF and NRAS genes are also significant risk factors in melanoma development. UV radiation plays a significant role in basal cell carcinoma (BCC) development by causing mutations in the Hedgehog (Hh) pathway, which dysregulates cell proliferation and survival. UV radiation can also induce the development of squamous cell carcinoma via mutations in the TP53 gene and upregulation of MMPs in the stroma layer of the skin.
PubMed: 38534742
DOI: 10.3390/cimb46030126 -
Molecular Cell Oct 2023UV irradiation induces "bulky" DNA photodimers such as (6-4)-photoproducts and cyclobutane pyrimidine dimers that are removed by nucleotide excision repair, a complex...
UV irradiation induces "bulky" DNA photodimers such as (6-4)-photoproducts and cyclobutane pyrimidine dimers that are removed by nucleotide excision repair, a complex process defective in the sunlight-sensitive and cancer-prone disease xeroderma pigmentosum. Some bacteria and lower eukaryotes can also repair photodimers by enzymatically simpler mechanisms, but such pathways have not been reported in normal human cells. Here, we have identified such a mechanism. We show that normal human cells can employ a DNA base excision repair process involving NTH1, APE1, PARP1, XRCC1, and FEN1 to rapidly remove a subset of photodimers at early times following UVC irradiation. Loss of these proteins slows the early rate of repair of photodimers in normal cells, ablates their residual repair in xeroderma pigmentosum cells, and increases UVC sensitivity ∼2-fold. These data reveal that human cells can excise photodimers using a long-patch base excision repair process that functions additively but independently of nucleotide excision repair.
Topics: Humans; Xeroderma Pigmentosum; DNA Repair; Pyrimidine Dimers; DNA Damage; DNA; Ultraviolet Rays; X-ray Repair Cross Complementing Protein 1
PubMed: 37816354
DOI: 10.1016/j.molcel.2023.09.013 -
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 -
Advanced Genetics (Hoboken, N.J.) Jun 2024Ultraviolet (UV) light is the most pervasive environmental mutagen and the primary cause of skin cancer. Genome sequencing of melanomas and other skin cancers has...
Ultraviolet (UV) light is the most pervasive environmental mutagen and the primary cause of skin cancer. Genome sequencing of melanomas and other skin cancers has revealed that the vast majority of somatic mutations in these tumors are cytosine-to-thymine (C>T) substitutions in dipyrimidine sequences, which, together with tandem CC>TT substitutions, comprise the canonical UV mutation "signature". These mutation classes are caused by DNA damage directly induced by UV absorption, namely cyclobutane pyrimidine dimers (CPDs) or 6-4 pyrimidine-pyrimidone photoproducts (6-4PP), which form between neighboring pyrimidine bases. However, many of the key driver mutations in melanoma do not fit this mutation signature, but instead are caused by T>A, T>C, C>A, or AC>TT substitutions, frequently occurring in non-dipyrimidine sequence contexts. This article describes recent studies indicating that UV light causes a more diverse spectrum of mutations than previously appreciated, including many of the mutation classes observed in melanoma driver mutations. Potential mechanisms for these diverse mutation signatures are discussed, including UV-induced pyrimidine-purine photoproducts and indirect DNA damage induced by UVA light. Finally, the article reviews recent findings indicating that human DNA polymerase eta normally suppresses these non-canonical UV mutation classes, which can potentially explain why canonical C>T substitutions predominate in human skin cancers.
PubMed: 38884048
DOI: 10.1002/ggn2.202300205 -
The Journal of Organic Chemistry Jul 2023The quest for simple systems achieving the photoreductive splitting of four-membered ring compounds is a matter of interest not only in organic chemistry but also in...
The quest for simple systems achieving the photoreductive splitting of four-membered ring compounds is a matter of interest not only in organic chemistry but also in biochemistry to mimic the activity of DNA photorepair enzymes. In this context, 8-oxoguanine, the main oxidatively generated lesion of guanine, has been shown to act as an intrinsic photoreductant by transferring an electron to bipyrimidine lesions and provoking their cycloreversion. But, in spite of appropriate photoredox properties, the capacity of guanine to repair cyclobutane pyrimidine dimer is not clearly established. Here, dyads containing the cyclobutane thymine dimer and guanine or 8-oxoguanine are synthesized, and their photoreactivities are compared. In both cases, the splitting of the ring takes place, leading to the formation of thymine, with a quantum yield 3.5 times lower than that for the guanine derivative. This result is in agreement with the more favored thermodynamics determined for the oxidized lesion. In addition, quantum chemistry calculations and molecular dynamics simulations are carried out to rationalize the crucial aspects of the overall cyclobutane thymine dimer photoreductive repair triggered by the nucleobase and its main lesion.
Topics: Pyrimidine Dimers; Cyclobutanes; Thymine; DNA; Guanine
PubMed: 37437138
DOI: 10.1021/acs.joc.3c00930 -
Frontiers in Immunology 2023Chronic metabolic changes relevant to human immunodeficiency virus type 1 (HIV-1) infection and in response to antiretroviral therapy (ART) remain undetermined....
BACKGROUND
Chronic metabolic changes relevant to human immunodeficiency virus type 1 (HIV-1) infection and in response to antiretroviral therapy (ART) remain undetermined. Moreover, links between metabolic dysfunction caused by HIV and immunological inflammation in long-term treated individuals have been poorly studied.
METHODS
Untargeted metabolomics and inflammatory cytokine levels were assessed in 47 HIV-infected individuals including 22 immunological responders (IRs) and 25 non-responders (INRs) before and after ART. The IRs and INRs were matched by age, gender, baseline viral load, and baseline CD4+T cell counts. Another 25 age-matched uninfected healthy individuals were also included as controls.
RESULTS
Among the 770 plasma compounds detected in the current study, significant changes were identified in lipids, nucleotides, and biogenic amino acids between HIV-infected patients and healthy controls. Principal Component Analysis (PCA) and the Random Forest (RF) model suggested that levels of selected metabolites could differentiate HIV-infected patients clearly from healthy controls. However, the metabolite profiles identified in our patients were similar, and only three metabolites, maltotetraose, N, N-dimethyl-5-aminovalerate, and decadienedioic acid (C10:2-DC), were different between IRs and INRs following long-term ART. The pathway enrichment analysis results revealed that disturbances in pyrimidine metabolism, sphingolipid metabolism, and purine metabolism after HIV infection and these changes did not recover to normal levels in healthy controls even with suppressive ART. Correlation analysis of the metabolism-immune network indicated that interleukin (IL)-10, D-dimer, vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and TNF-RII were positively correlated with most of the significantly changed lipid and amino acid metabolites but negatively correlated with metabolites in nucleotide metabolism.
CONCLUSIONS
Significant changes in many metabolites were observed in HIV-infected individuals before and after ART regardless of their immunological recovery status. The disturbed metabolic profiles of lipids and nucleotides in HIV infection did not recover to normal levels even after long-term ART. These changes are correlated with modified cytokines and biomarkers of chronic non-AIDS events, warranting tryout of interventions other than ART.
Topics: Humans; HIV Infections; HIV-1; CD4-Positive T-Lymphocytes; Lipids; Nucleotides
PubMed: 37828979
DOI: 10.3389/fimmu.2023.1254155 -
Heliyon Mar 2024The sensitivity of crops to ultraviolet B (UVB, 280-315 nm) radiation varies significantly. Plants' sensitivity to UVB is heavily influenced by the activity of the... (Review)
Review
The sensitivity of crops to ultraviolet B (UVB, 280-315 nm) radiation varies significantly. Plants' sensitivity to UVB is heavily influenced by the activity of the enzyme cyclobutane pyrimidine dimer (CPD) photolyase, which fixes UVB-induced CPDs. Crops grown in tropical areas with high level of UVB radiation, like from Africa and ssp. rice from Bengal, are more sensitive to UVB radiation and could suffer more as a result of rising UVB levels on the earth's surface. Therefore, creating crops that can withstand high UVB is crucial in tropical regions. There is, however, little information on current techniques for breeding UVB-resistant plants. The most recent techniques for producing UVB-resistant crops are presented in this review. The use of DNA methylation, boosting the antioxidant system, regulating the expression of micro-RNA396, and overexpressing CPD photolyase in transgenic plants are some of the methods that are discussed. CPD photolyase overexpression in transgenic plants is the most popular technique for producing UVB-resistant rice. The study also offers several strategies for creating UVB-resistant plants using gene editing techniques. To feed the world's rapidly expanding population, researchers can use the information from this study to improve food production.
PubMed: 38509919
DOI: 10.1016/j.heliyon.2024.e27806