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oai:repisalud.isciii.es:20.500.12105/253602025-12-18T13:00:46Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Pintado-Berninches, Laura author Fernandez-Varas, Beatriz author Benitez-Buelga, Carlos author Manguan-Garcia, Cristina author Serrano-Benitez, Almudena author Iarriccio, Laura author Carrillo, Jaime author Guenechea, Guillermo author Egusquiaguirre, Susana P author Pedraz, Jose-Luis author Hernández, Rosa M author Igartua, Manoli author Arias-Salgado, Elena G author Cortes-Ledesma, Felipe author Sastre, Leandro author Perona, Rosario author Pintado-Berninches, Laura author Fernandez-Varas, Beatriz author Benitez-Buelga, Carlos author Manguan-Garcia, Cristina author Serrano-Benitez, Almudena author Iarriccio, Laura author Carrillo, Jaime author Guenechea, Guillermo author Egusquiaguirre, Susana P author Pedraz, Jose-Luis author Hernández, Rosa M author Igartua, Manoli author Arias-Salgado, Elena G author Sastre, Leandro author Perona, Rosario author 2019-10 Ataxia telangiectasia (AT) is a genetic disease caused by mutations in the ATM gene but the mechanisms underlying AT are not completely understood. Key functions of the ATM protein are to sense and regulate cellular redox status and to transduce DNA double-strand break signals to downstream effectors. ATM-deficient cells show increased ROS accumulation, activation of p38 protein kinase, and increased levels of DNA damage. GSE24.2 peptide and a short derivative GSE4 peptide corresponding to an internal domain of Dyskerin have proved to induce telomerase activity, decrease oxidative stress, and protect from DNA damage in dyskeratosis congenita (DC) cells. We have found that expression of GSE24.2 and GSE4 in human AT fibroblast is able to decrease DNA damage, detected by γ-H2A.X and 53BP1 foci. However, GSE24.2/GSE4 expression does not improve double-strand break signaling and repair caused by the lack of ATM activity. In contrast, they cause a decrease in 8-oxoguanine and OGG1-derived lesions, particularly at telomeres and mitochondrial DNA, as well as in reactive oxygen species, in parallel with increased expression of SOD1. These cells also showed lower levels of IL6 and decreased p38 phosphorylation, decreased senescence and increased ability to divide for longer times. Additionally, these cells are more resistant to treatment with H0 and the radiomimetic-drug bleomycin. Finally, we found shorter telomere length (TL) in AT cells, lower levels of TERT expression, and telomerase activity that were also partially reverted by GSE4. These observations suggest that GSE4 may be considered as a new therapy for the treatment of AT that counteracts the cellular effects of high ROS levels generated in AT cells and in addition increases telomerase activity contributing to increased cell proliferation. Cell Death Differ . 2019 Oct;26(10):1998-2014 Cell Death and Differentiation 30670828 https://hdl.handle.net/20.500.12105/25360 LINKED DYSKERATOSIS-CONGENITA NEURAL STEM-CELLS DNA-DAMAGE CELLULAR-RESPONSE ATM STRESS ACTIVATION SENESCENCE GENE PATHOGENESIS GSE4 peptide suppresses oxidative and telomere deficiencies in ataxia telangiectasia patient cells.