Pintado-Berninches, LauraFernandez-Varas, BeatrizBenitez-Buelga, CarlosManguan-Garcia, CristinaSerrano-Benitez, AlmudenaIarriccio, LauraCarrillo, JaimeGuenechea, GuillermoEgusquiaguirre, Susana PPedraz, Jose-LuisHernández, Rosa MIgartua, ManoliArias-Salgado, Elena GCortes-Ledesma, FelipeSastre, LeandroPerona, RosarioPintado-Berninches, LauraFernandez-Varas, BeatrizBenitez-Buelga, CarlosManguan-Garcia, CristinaSerrano-Benitez, AlmudenaIarriccio, LauraCarrillo, JaimeGuenechea, GuillermoEgusquiaguirre, Susana PPedraz, Jose-LuisHernández, Rosa MIgartua, ManoliArias-Salgado, Elena GSastre, LeandroPerona, Rosario2024-10-292024-10-292019-10Cell Death Differ . 2019 Oct;26(10):1998-2014https://hdl.handle.net/20.500.12105/25360RP laboratory is funded by grant P14-01495 and P17-01401 (Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain supported by FEDER funds) and CIBER 576/805_ER16PE06P2016 supported by FEDER funds. GG grant "Ministerio de Economia, Comercio y Competitividad y Fondo Europeo de Desarrollo Regional (FEDER)" (SAF2015-68073-R). CM-G is granted by the CIBERER. Work in FC-L laboratory is funded with grants from the Spanish Government (SAF2014-55532-R, Ministerio de Economia, Industria y Competitividad), the regional Andalusian Government (CVI-7948), the Fundacion Ramon Areces (XVII Convocatoria Ciencias de la Vida y Materia), the European Research Council (ERC-CoG-2014-647359), and with a Predoctoral Fellowship from AEFAT (Asociacion Espanola Familia Ataxia Telangiectasia) to AS-B. BER OGG1 was kindly provided by Professor Thomas Helleday's Lab, Karolinska Institutet, Sweden. We gratefully acknowledge to Dr. Antonio Cuadrado for the SOD1 promoter, to Monica MartinezBelinchon, and Dolores Morales-Garcia for valuable help in the confocal studies. We also acknowledge Ana Sastre-Perona for useful comments.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.engVoRhttp://creativecommons.org/licenses/by/4.0/LINKED DYSKERATOSIS-CONGENITANEURAL STEM-CELLSDNA-DAMAGECELLULAR-RESPONSEATMSTRESSACTIVATIONSENESCENCEGENEPATHOGENESISAttribution 4.0 International3067082826101998-2014Cell Death and Differentiationopen access