Novel role of p53 in maintaining mitochondrial genetic stability through interaction with DNA Pol γ

Achanta, Geetha; Sasaki, Ryohei; Li, Feng; Carew, Jennifer S.; Lu, Weiqin; Pélicano, Hélène; Keating, Michael J.; Huang, Peng

doi:10.1038/sj.emboj.7600819

Cited by 259 publications

(247 citation statements)

References 43 publications

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“…p53 interacts with mtDNA‐associated proteins such as CHCHD4, OGG1, Parkin, POLG, and TFAM (Achanta & Huang, 2004; Achanta et al ., 2005; and Wong et al ., 2009; Hoshino et al ., 2013; Zhuang et al ., 2013). In conjunction with partner molecules, p53 is involved in modulating mtDNA replication and transcription, maintaining mtDNA stability, and repairing mtDNA.…”

Section: Discussionmentioning

confidence: 98%

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

et al. 2017

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SummaryAlzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is poorly understood. Sirtuins (SIRT, silent mating type information regulation 2 homolog in yeast) are NAD‐dependent histone deacetylases involved in aging and longevity. The objective of this study was to investigate the relationship between SIRT3 and mitochondrial function and neuronal activity in AD. SIRT3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac‐p53 K320 was significantly increased in AD mitochondria. SIRT3 prevented p53‐induced mitochondrial dysfunction and neuronal damage in a deacetylase activity‐dependent manner. Notably, mitochondrially targeted p53 (mito‐p53) directly reduced mitochondria DNA‐encoded ND2 and ND4 gene expression resulting in increased reactive oxygen species (ROS) and reduced mitochondrial oxygen consumption. ND2 and ND4 gene expressions were significantly decreased in patients with AD. p53‐ChIP analysis verified the presence of p53‐binding elements in the human mitochondrial genome and increased p53 occupancy of mitochondrial DNA in AD. SIRT3 overexpression restored the expression of ND2 and ND4 and improved mitochondrial oxygen consumption by repressing mito‐p53 activity. Our results indicate that SIRT3 dysfunction leads to p53‐mediated mitochondrial and neuronal damage in AD. Therapeutic modulation of SIRT3 activity may ameliorate mitochondrial pathology and neurodegeneration in AD.

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Section: Discussionmentioning

confidence: 98%

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

et al. 2017

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“…Importantly, these p53-null CLL cells remain sensitive to PEITC. Since the loss of p53 is known to promote genetic instability and mitochondrial dysfunction, 49 which not only confers drug resistance but may also promote ROS production, 14 it is conceivable that the p53-null CLL cells may have elevated ROS generation and would be highly sensitive to PEITC. Since the loss of p53 is prevalent in cancer and associated with resistance to many standard therapeutic agents, 50 the novel ROS-mediated strategy using agents such as PEITC may have potentially broad clinical implications.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the loss of p53 seems to promote mtDNA mutations and enhance ROS production in cultured cell lines. 14 Multiple mechanisms, including mitochondrial dysfunction and metabolic stress, likely contribute to ROS stress in CLL cells. From the therapeutic standpoint, one important question is how to use the elevated ROS stress in CLL cells to develop effective new strategies to kill the leukemia cells.…”

Section: Introductionmentioning

confidence: 99%

Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism

Trachootham

Zhang

et al. 2008

Blood

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Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, and resistance to fludarabine-based therapies is a major challenge in CLL treatment. Because CLL cells are known to have elevated levels of reactive oxygen species (ROS), we aimed to test a novel ROS-mediated strategy to eliminate fludarabine-resistant CLL cells based on this redox alteration. Using primary CLL cells and normal lymphocytes from patients (n ‫؍‬ 58) and healthy subjects (n ‫؍‬ 12), we showed that both fludarabineresistant and -sensitive CLL cells were highly sensitive to ␤-phenylethyl isothiocyanate (PEITC) with mean IC 50 values of 5.4 M and 5.1 M, respectively. Normal lymphocytes were significantly less sensitive to PEITC (IC 50 ‫؍‬ 27 M, P < .001). CLL cells exhibited intrinsically higher ROS level and lower cellular glutathione, which were shown to be the critical determinants of CLL sensitivity to PEITC. Exposure of CLL cells to PEITC induced severe glutathione depletion, ROS accumulation, and oxidation of mitochondrial cardiolipin leading to massive cell death. Such ROS stress also caused deglutathionylation of MCL1, followed by a rapid degradation of this cell survival molecule. Our study demonstrated that the natural compound PEITC is effective in eliminating fludarabine-resistant CLL cells through a redox-mediated mechanism with low toxicity to normal lymphocytes, and warrants further clinical evaluation.

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“…Wild type p53 has been reported to modulate mitochondrial respiration, as well as enhancing apoptosis. It also suppresses mtDNA mutagenesis and regulates mtDNA copy number [35][36][37]. To determine the fidelity of the TP53 gene, we used direct DNA sequencing of the parent/HNO cell lines.…”

Section: Somatic Mutations In Tp53 Genementioning

confidence: 99%

Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism

et al. 2012

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Nutrient deprivation and reactive oxygen species (ROS) play an important role in breast cancer mitochondrial adaptation. Adaptations to these conditions allow cells to survive in the stressful microenvironment of the tumor bed. This study is directed at defining the consequences of High Nitric Oxide (HNO) exposure to mitochondria in human breast cancer cells. The breast cancer cell line BT-20 (parent) was adapted to HNO as previously reported, resulting in the BT-20-HNO cell line. Both cell lines were analyzed by a variety of methods including MTT, LDH leakage assay, DNA sequencing, and Western blot analysis. The LDH assay and the gene chip data showed that BT-20-HNO was more prone to use the glycolytic pathway than the parent cell line. The BT-20-HNO cells were also more resistant to the apoptotic inducing agent salinomycin, which suggests that p53 may be mutated in these cells. Polymerase chain reaction (PCR) followed by DNA sequencing of the p53 gene showed that it was, in fact, mutated at the DNA-binding site (L194F). Western blot analysis showed that p53 was significantly upregulated in these cells. These results suggest that free radicals, such as nitric oxide (NO), pressure human breast tumor cells to acquire an aggressive phenotype and resistance to apoptosis. These data collectively provide a mechanism by which the dysregulation of ROS in the mitochondria of breast cancer cells can result in DNA damage.Keywords Breast cancer . Nitric oxide . p53 . Reactive oxygen species (ROS) . Glycolysis and apoptosis . Aerobic and anaerobic metabolisms

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Novel role of p53 in maintaining mitochondrial genetic stability through interaction with DNA Pol γ

Cited by 259 publications

References 43 publications

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism

Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism

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