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 H202 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.

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RP 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 Economía, 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 Economía, Industria y Competitividad), the regional Andalusian Government (CVI-7948), the Fundación Ramón Areces (XVII Convocatoria Ciencias de la Vida y Materia), the European Research Council (ERC-CoG-2014-647359), and with a Predoctoral Fellowship from AEFAT (Asociación Española 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 Martinez-Belinchon, and Dolores Morales-Garcia for valuable help in the confocal studies. We also acknowledge Ana Sastre-Perona for useful comments.

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Author notes

  1. These authors contributed equally: Leandro Sastre, Rosario Perona


  1. Instituto de Investigaciones Biomédicas CSIC/UAM, IDiPaz, C/ Arturo Duperier, 4, 28029, Madrid, Spain

    • Laura Pintado-Berninches
    • , Beatriz Fernandez-Varas
    • , Cristina Manguan-Garcia
    • , Laura Iarriccio
    • , Jaime Carrillo
    • , Elena G. Arias-Salgado
    • , Leandro Sastre
    •  & Rosario Perona
  2. Advanced Medical Projects, Madrid, Spain

    • Laura Pintado-Berninches
    • , Laura Iarriccio
    •  & Elena G. Arias-Salgado
  3. National Center for Cancer Research, CNIO, Madrid, Spain

    • Carlos Benitez-Buelga
  4. CIBER de Enfermedades Raras, Madrid, Spain

    • Cristina Manguan-Garcia
    • , Guillermo Guenechea
    • , Leandro Sastre
    •  & Rosario Perona
  5. Centro Andaluz de Biologia Molecular y Medicina regenerativa (CABIMER) - CSIC, Universidad de Sevilla, Universidad Pablo de Olavide, Sevilla, Spain

    • Almudena Serrano-Benitez
    •  & Felipe Cortés-Ledesma
  6. Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain

    • Guillermo Guenechea
  7. Advanced Therapies Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain

    • Guillermo Guenechea
  8. NanoBioCel Group, Laboratory of Pharmaceutics, University of the Basque Country, School of Pharmacy, Vitoria-Gasteiz, Spain

    • Susana P. Egusquiaguirre
    • , Jose-Luis Pedraz
    • , Rosa M. Hernández
    •  & Manoli Igartua
  9. Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain

    • Susana P. Egusquiaguirre
    • , Jose-Luis Pedraz
    • , Rosa M. Hernández
    •  & Manoli Igartua


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Correspondence to Rosario Perona.

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