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Programmed cell death 6, a novel p53-responsive gene, targets to the nucleus in the apoptotic response to DNA damage
Kazuho Suzuki1, Nurmaa Dashzeveg, Zheng-Guang Lu
1Department of Molecular Genetics, Tokyo Medical and Dental University, Japan.
Abstract:
The cellular response to genotoxic stress is multifaceted in nature. Following DNA damage, the tumor suppressor gene p53 activates and plays critical roles in cell cycle arrest, activation of DNA repair and in the event of irreparable damage, induction of apoptosis. The breakdown of apoptosis causes the accumulation of mutant cells. The elucidation of the mechanism for the p53-dependent apoptosis will be crucial in applying the strategy for cancer patients. However, the mechanism of p53-dependent apoptosis remains largely unclear. Here, we carried out ChIP followed by massively parallel DNA sequencing assay (ChIP-seq) to uncover mechanisms of apoptosis. Using ChIP-seq, we identified PDCD6 as a novel p53-responsive gene. We determined putative p53-binding sites that are important for p53 regulation in response to DNA damage in the promoter region of PDCD6. Knockdown of PDCD6 suppressed p53-dependent apoptosis. We also observed that cytochrome c release and the cleavage of PARP by caspase-3 were suppressed by depletion of PDCD6. We further observed that PDCD6 localizes in the nucleus in response to DNA damage. We identified the nuclear localization signal of PDCD6 and, importantly, the nuclear accumulation of PDCD6 significantly induced apoptosis after genotoxic stress. Therefore, we conclude that a novel p53-responsive gene PDCD6 is accumulated in the nucleus and induces apoptosis in response to DNA damage.
Insights
The tumor suppressor p53 induces apoptosis to eliminate damaged cells. We discovered PDCD6, a novel p53-responsive gene, accumulates in the nucleus and promotes apoptosis following DNA damage.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Cellular response to genotoxic stress involves p53, a tumor suppressor crucial for DNA repair, cell cycle arrest, and apoptosis.
- Dysregulation of apoptosis leads to mutant cell accumulation, contributing to cancer development.
- Understanding p53-dependent apoptosis mechanisms is vital for cancer therapy strategies.
Purpose of the Study:
- To elucidate the unclear mechanisms of p53-dependent apoptosis.
- To identify novel genes regulated by p53 in response to DNA damage.
- To investigate the role of newly identified genes in the apoptotic pathway.
Main Methods:
- Chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq) to identify p53-binding sites and target genes.
- Gene knockdown experiments to assess the function of identified genes.
- Confocal microscopy to determine protein localization.
- Analysis of apoptosis markers like cytochrome c release and PARP cleavage.
Main Results:
- ChIP-seq identified PDCD6 (Programmed Cell Death 6) as a novel p53-responsive gene.
- Putative p53-binding sites were found in the PDCD6 promoter, regulating its expression after DNA damage.
- Knockdown of PDCD6 inhibited p53-dependent apoptosis, cytochrome c release, and PARP cleavage.
- PDCD6 was observed to accumulate in the nucleus upon genotoxic stress, mediated by its nuclear localization signal.
Conclusions:
- PDCD6 is a novel p53-responsive gene that plays a critical role in inducing apoptosis.
- Nuclear accumulation of PDCD6 following genotoxic stress promotes apoptosis.
- PDCD6 represents a potential therapeutic target for enhancing cancer cell apoptosis.
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