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Cell Death Differ. 2019 Jan 22. doi: 10.1038/s41418-018-0272-7. [Epub ahead of print]

GSE4 peptide suppresses oxidative and telomere deficiencies in ataxia telangiectasia patient cells.

Author information

Instituto de Investigaciones Biomédicas CSIC/UAM, IDiPaz, C/ Arturo Duperier, 4, 28029, Madrid, Spain.
Advanced Medical Projects, Madrid, Spain.
National Center for Cancer Research, CNIO, Madrid, Spain.
CIBER de Enfermedades Raras, Madrid, Spain.
Centro Andaluz de Biologia Molecular y Medicina regenerativa (CABIMER) - CSIC, Universidad de Sevilla, Universidad Pablo de Olavide, Sevilla, Spain.
Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.
Advanced Therapies Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain.
NanoBioCel Group, Laboratory of Pharmaceutics, University of the Basque Country, School of Pharmacy, Vitoria-Gasteiz, Spain.
Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain.
Instituto de Investigaciones Biomédicas CSIC/UAM, IDiPaz, C/ Arturo Duperier, 4, 28029, Madrid, Spain.
CIBER de Enfermedades Raras, Madrid, Spain.


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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