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 language | English |
|---|---|
| Pages (from-to) | 1200-1208 |
| Number of pages | 9 |
| Journal | DNA Repair |
| Volume | 9 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 10 2010 |
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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 journal › Article
}
TY - JOUR
T1 - A novel defect in mitochondrial p53 accumulation following DNA damage confers apoptosis resistance in Ataxia Telangiectasia and Nijmegen Breakage Syndrome T-cells
AU - Turinetto, Valentina
AU - Porcedda, Paola
AU - Minieri, Valentina
AU - Orlando, Luca
AU - Lantelme, Erica
AU - Accomasso, Lisa
AU - Amoroso, Antonio
AU - De Marchi, Mario
AU - Zannini, Laura
AU - Delia, Domenico
AU - Giachino, Claudia
PY - 2010/11/10
Y1 - 2010/11/10
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Ataxia Telangiectasia
KW - DNA damage
KW - Nijmegen Breakage Syndrome
KW - P53
UR - http://www.scopus.com/inward/record.url?scp=78049375911&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78049375911&partnerID=8YFLogxK
U2 - 10.1016/j.dnarep.2010.09.003
DO - 10.1016/j.dnarep.2010.09.003
M3 - Article
C2 - 20947454
AN - SCOPUS:78049375911
VL - 9
SP - 1200
EP - 1208
JO - DNA Repair
JF - DNA Repair
SN - 1568-7864
IS - 11
ER -