ABSTRACT
Telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) constitute the core telomerase enzyme that maintains the length of telomeres. Telomere maintenance is affected in a broad range of cancer and degenerative disorders. Taking advantage of gain- and loss-of-function approaches, we show that Argonaute 2 (AGO2) promotes telomerase activity and stimulates the association between TERT and TERC AGO2 depletion results in shorter telomeres as well as in lower proliferation rates in vitro and in vivo We also demonstrate that AGO2 interacts with TERC and with a newly identified sRNA (terc-sRNA), arising from the H/ACA box of TERC Notably, terc-sRNA is sufficient to enhance telomerase activity when overexpressed. Analyses of sRNA-Seq datasets show that terc-sRNA is detected in primary human tissues and increases in tumors as compared to control tissues. Collectively, these data uncover a new layer of complexity in the regulation of telomerase activity by AGO2 and might lay the foundation for new therapeutic targets in tumors and telomere diseases.
Subject(s)
Argonaute Proteins/metabolism , RNA/genetics , RNA/metabolism , Telomerase/metabolism , Animals , Argonaute Proteins/genetics , Cell Line, Tumor , Cell Proliferation , Disease Models, Animal , Enzyme Activation , Gene Expression , Genetic Loci , Heterografts , Humans , Mice , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Nucleic Acid Conformation , Protein Binding , RNA/chemistry , Telomerase/chemistry , Telomerase/geneticsABSTRACT
AIMS: Oxidative stress increase is a key event for development of sensitivity-related illnesses (SRIs). The aim of this work was to evaluate the influence of a genetic variant in the antioxidant enzyme glutathione peroxidase (GPx1) on oxidative stress development in SRIs. MAIN METHODS: GPx1 rs1800668 genotype, as well as glutathione, ubiquinone, and DNA damage were assessed in 34 SRI patients and 36 healthy subjects. KEY FINDINGS: Total glutathione, reduced/oxidized glutathione, and ubiquinone were significantly decreased in cases compared with controls, while DNA fragmentation was significantly increased in patients. However, these differences were not associated to GPx1 genetic background. SIGNIFICANCE: GPx1 rs1800668 polymorphism does not play a major role in SRI-related oxidative stress development.
Subject(s)
DNA Damage , Glutathione Peroxidase/genetics , Multiple Chemical Sensitivity/genetics , Oxidative Stress , Polymorphism, Genetic , Adult , Female , Genotype , Glutathione Peroxidase/metabolism , Humans , Male , Multiple Chemical Sensitivity/metabolism , Young Adult , Glutathione Peroxidase GPX1ABSTRACT
Oxidative stress and inflammation play a pathogenetic role in idiopathic environmental intolerances (IEI), namely, multiple chemical sensitivity (MCS), fibromyalgia (FM), and chronic fatigue syndrome (CFS). Given the reported association of nitric oxide synthase (NOS) gene polymorphisms with inflammatory disorders, we aimed to investigate the distribution of NOS2A -2.5 kb (CCTTT) n as well as Ser608Leu and NOS3 -786T>C variants and their correlation with nitrite/nitrate levels, in a study cohort including 170 MCS, 108 suspected MCS (SMCS), 89 FM/CFS, and 196 healthy subjects. Patients and controls had similar distributions of NOS2A Ser608Leu and NOS3 -786T>C polymorphisms. Interestingly, the NOS3 -786TT genotype was associated with increased nitrite/nitrate levels only in IEI patients. We also found that the NOS2A -2.5 kb (CCTTT)11 allele represents a genetic determinant for FM/CFS, and the (CCTTT)16 allele discriminates MCS from SMCS patients. Instead, the (CCTTT)8 allele reduces by three-, six-, and tenfold, respectively, the risk for MCS, SMCS, and FM/CFS. Moreover, a short number of (CCTTT) repeats is associated with higher concentrations of nitrites/nitrates. Here, we first demonstrate that NOS3 -786T>C variant affects nitrite/nitrate levels in IEI patients and that screening for NOS2A -2.5 kb (CCTTT) n polymorphism may be useful for differential diagnosis of various IEI.
