A novel defect in mitochondrial p53 accumulation following DNA damage confers apoptosis resistance in Ataxia Telangiectasia and Nijmegen Breakage Syndrome T-cells

Valentina Turinetto, Paola Porcedda, Valentina Minieri, Luca Orlando, Erica Lantelme, Lisa Accomasso, Antonio Amoroso, Mario De Marchi, Laura Zannini, Domenico Delia, Claudia Giachino

Research output: Contribution to journalArticle

Abstract

We have previously shown that whereas T-cells from normal individuals undergo accumulation of p53 and apoptosis when treated with the genotoxic agent Actinomycin D (ActD), those from Ataxia Telangiectasia (AT) and Nijmegen Breakage Syndrome (NBS) patients resist ActD-induced apoptosis [1]. We have now found similar resistance by the p53-null Jurkat T-cell line and by siRNA p53-knockdown normal T-cells. This evidence that ActD initiates a p53-dependent apoptotic responce prompted us to look for defective p53 accumulation by AT and NBS T-cells. Surprisingly the total p53 level was only slightly reduced compared to normal T cells but its intracellular localization was highly defective: p53 was poorly accumulated in the cytosol and nearly undetectable in mitochondria. In accordance with the dependence of ActD-induced apoptosis on a mitochondrial p53 function, in control T-cells specific inhibition of mitochondrial p53 translocation with μ pifithrin reduced apoptosis by 86%, whereas treatment with α pifithrin, which blocks p53-mediated transcription, had no effect. We also showed that nuclear export is not required for mitochondrial p53 translocation. Observation of an altered p53 ubiquitination pattern and Mdm2 accumulation in ActD-treated AT and NBS T-cells provided a mechanistic link to their defective extranuclear p53 localization. Our results disclose an undescribed defect in mitochondrial p53 accumulation in AT and NBS T-cells that makes them resistant to apoptosis following unrepairable DNA damage.

Original languageEnglish
Pages (from-to)1200-1208
Number of pages9
JournalDNA Repair
Volume9
Issue number11
DOIs
Publication statusPublished - Nov 10 2010

Fingerprint

Nijmegen Breakage Syndrome
Ataxia Telangiectasia
T-cells
DNA Damage
Apoptosis
Dactinomycin
T-Lymphocytes
Defects
DNA
Null Lymphocytes
Mitochondria
Jurkat Cells
Cell Nucleus Active Transport
Ubiquitination
Transcription
Cytosol
Small Interfering RNA
Observation
Cell Line

Keywords

  • Apoptosis
  • Ataxia Telangiectasia
  • DNA damage
  • Nijmegen Breakage Syndrome
  • P53

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

A novel defect in mitochondrial p53 accumulation following DNA damage confers apoptosis resistance in Ataxia Telangiectasia and Nijmegen Breakage Syndrome T-cells. / Turinetto, Valentina; Porcedda, Paola; Minieri, Valentina; Orlando, Luca; Lantelme, Erica; Accomasso, Lisa; Amoroso, Antonio; De Marchi, Mario; Zannini, Laura; Delia, Domenico; Giachino, Claudia.

In: DNA Repair, Vol. 9, No. 11, 10.11.2010, p. 1200-1208.

Research output: Contribution to journalArticle

Turinetto, V, Porcedda, P, Minieri, V, Orlando, L, Lantelme, E, Accomasso, L, Amoroso, A, De Marchi, M, Zannini, L, Delia, D & Giachino, C 2010, 'A novel defect in mitochondrial p53 accumulation following DNA damage confers apoptosis resistance in Ataxia Telangiectasia and Nijmegen Breakage Syndrome T-cells', DNA Repair, vol. 9, no. 11, pp. 1200-1208. https://doi.org/10.1016/j.dnarep.2010.09.003
Turinetto, Valentina ; Porcedda, Paola ; Minieri, Valentina ; Orlando, Luca ; Lantelme, Erica ; Accomasso, Lisa ; Amoroso, Antonio ; De Marchi, Mario ; Zannini, Laura ; Delia, Domenico ; Giachino, Claudia. / A novel defect in mitochondrial p53 accumulation following DNA damage confers apoptosis resistance in Ataxia Telangiectasia and Nijmegen Breakage Syndrome T-cells. In: DNA Repair. 2010 ; Vol. 9, No. 11. pp. 1200-1208.
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