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Premature aging syndrome in ataxia telangiectasia patients

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Abstract

Ataxia telangiectasia (AT) is a genetic disorder caused by the mutation of the atm gene. It is characterized by progressive neurological abnormalities in combination with oculocutaneous telangiectasias, immunodeficiency, and increased frequency of malignancy. Cells of AT patients display increased radiosensitivity and premature aging markers, including shortened telomer length beginning at birth and limited proliferation potential. We studied radiosensitivity (at a dose 2 Gy) and the manifestation of premature aging markers in cultured skin fibroblasts derived from two unrelated AT patients and their heterozygous parents. We have shown that all the markers studied, i.e., HP1-γ, histone H2AX phosphorylated for serine-139 (γ-H2AX) and foci of 53BP1 protein, indicate the premature aging of the cells of both patients and their blood relatives. However, cells of heterozygous carriers express premature aging to a lesser extent. A study of the repair process (the amount of γ-H2AX and the number of cells with 53BP1 foci in their nuclei) after X-ray irradiation showed that patients’ cells only halfway completed repairs, even 24 h after irradiation, while the healthy donor cells completed repairs in 24 h. In cells from atm heterozygous donors, DNA repair was also slower. Heterozygous cells also differ reliably from healthy donor cells. Only amounts of p21Waf1/Cip1 protein, an inhibitor of cyclin-dependent kinases, in heterozygous cells do not differ from normal cells. However, the patients’ cells differ significantly. It was found that the mutation of the atm gene was related to the suppression of the reparation of DNA double-strand breaks (DSBs), which is in good agreement with increased radiosensitivity and premature aging in AT families at the cellular level.

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Authors and Affiliations

  1. Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia

    E. A. Polubotko, N. V. Smirnova, N. M. Pleskach, V. M. Mikhelson & I. M. Spivak

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  1. E. A. Polubotko
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  2. N. V. Smirnova
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  3. N. M. Pleskach
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  4. V. M. Mikhelson
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  5. I. M. Spivak
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Correspondence to E. A. Polubotko.

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Original Russian Text © E.A. Polubotko, N.V. Smirnova, N.M. Pleskach, V.M. Mikhelson, I.M. Spivak, 2009, published in Tsitologiya, Vol. 51, No. 8, 2009, pp. 712–718.

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Polubotko, E.A., Smirnova, N.V., Pleskach, N.M. et al. Premature aging syndrome in ataxia telangiectasia patients. Cell Tiss. Biol. 3, 491–496 (2009). https://doi.org/10.1134/S1990519X09050125

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  • DOI: https://doi.org/10.1134/S1990519X09050125

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