Dataset Information

Enhanced pro-apoptosis gene signature following the activation of TAp63α in oocytes upon γ irradiation.

ABSTRACT: Specialized surveillance mechanisms are essential to maintain the genetic integrity of germ cells, which are not only the source of all somatic cells but also of the germ cells of the next generation. DNA damage and chromosomal aberrations are, therefore, not only detrimental for the individual but affect the entire species. In oocytes, the surveillance of the structural integrity of the DNA is maintained by the p53 family member TAp63α. The TAp63α protein is highly expressed in a closed and inactive state and gets activated to the open conformation upon the detection of DNA damage, in particular DNA double-strand breaks. To understand the cellular response to DNA damage that leads to the TAp63α triggered oocyte death we have investigated the RNA transcriptome of oocytes following irradiation at different time points. The analysis shows enhanced expression of pro-apoptotic and typical p53 target genes such as CDKn1a or Mdm2, concomitant with the activation of TAp63α. While DNA repair genes are not upregulated, inflammation-related genes become transcribed when apoptosis is initiated by activation of STAT transcription factors. Furthermore, comparison with the transcriptional profile of the ΔNp63α isoform from other studies shows only a minimal overlap, suggesting distinct regulatory programs of different p63 isoforms.

SUBMITTER: Fester N

PROVIDER: S-EPMC8897389 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Enhanced pro-apoptosis gene signature following the activation of TAp63α in oocytes upon γ irradiation.

Fester Niclas N Zielonka Elisabeth E Goldmann Jakob J Frombach Ann-Sophie AS Müller-Kuller Uta U Gutfreund Niklas N Riegel Kristina K Smits Jos G A JGA Schleiff Enrico E Rajalingam Krishnaraj K Zhou Huiqing H Simm Stefan S Dötsch Volker V

Cell death & disease 20220304 3

Specialized surveillance mechanisms are essential to maintain the genetic integrity of germ cells, which are not only the source of all somatic cells but also of the germ cells of the next generation. DNA damage and chromosomal aberrations are, therefore, not only detrimental for the individual but affect the entire species. In oocytes, the surveillance of the structural integrity of the DNA is maintained by the p53 family member TAp63α. The TAp63α protein is highly expressed in a closed and ina ...[more]

PMID: 35246516

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Project description:Standard cytotoxic cancer treatments, such as radiation, can damage and deplete the supply of oocytes stored within the ovary, which predisposes females to infertility and premature menopause later in life. The mechanisms by which radiation induces oocyte damage have not been completely elucidated. The objective of this study was to determine if γ-irradiation changes mitochondrial characteristics in oocytes, possibly contributing to a reduction in oocyte number and quality. Immature oocytes were collected from postnatal day (PN) 9-11 C57Bl6 mice 3, 6 and 24 hours after 0.1 Gy γ-irradiation to monitor acute mitochondrial changes. Oocytes were classified as small (>20 µm) or growing (40-60 µm). Mitochondrial membrane potential was lost in 20% and 44% of small oocytes (~20 µm) at 3 and 6 hours after γ-irradiation, respectively, consistent with the induction of apoptosis. However, mitochondrial mass, distribution and membrane potential in the surviving small oocytes were similar to the non-irradiated controls at both time points. At 24 hours after γ-irradiation, all mitochondrial parameters analysed within immature oocytes were similar to untreated controls. Mitochondrial parameters within growing oocytes were also similar to untreated controls. When mice were superovulated more than 3 weeks after γ-irradiation, there was a significant reduction in the number of mature oocytes harvested compared to controls (Control 18 ± 1 vs 0.1 Gy 4 ± 1, n = 6/16 mice, p < 0.05). There was a slight reduction in mitochondrial mass in mature oocytes after γ-irradiation, though mitochondrial localization, mtDNA copy number and ATP levels were similar between groups. In summary, this study shows that γ-irradiation of pre-pubertal mice is associated with loss of mitochondrial membrane potential in a significant proportion of small immature oocytes and a reduction in the number of mature oocytes harvested from adult mice. Furthermore, these results suggest that immature oocytes that survive γ-irradiation and develop through to ovulation contain mitochondria with normal characteristics. Whether the oocytes that survive radiation and eventually undergo meiosis can support fertility remains to be determined.

Project description:Molt-4 leukemia cells undergo p53-dependent apoptosis accompanied by accumulation of de novo ceramide after 14 hours of γ-irradiation. In order to identify the potential mediators involved in ceramide accumulation and the cell death response, differentially expressed genes were identified by Affymetrix Microarray Analysis. Molt-4-LXSN cells, expressing wild type p53, and p53-deficient Molt-4-E6 cells were irradiated and harvested at 3 and 8 hours post-irradiation. Human genome U133 plus 2.0 array containing >47,000 transcripts was used for gene expression profiling. From over 10,000 probes, 281 and 12 probes were differentially expressed in Molt-4-LXSN and Molt-4-E6 cells, respectively. Data analysis revealed 63 (upregulated) and 20 (downregulated) genes (>2 fold) in Molt-4-LXSN at 3 hours and 140 (upregulated) and 21 (downregulated) at 8 hours post-irradiation. In Molt-4-E6 cells, 5 (upregulated) genes each were found at 3 hours and 8 hours, respectively. In Molt-4-LXSN cells, a significant fraction of the genes with altered expression at 3 hours were found to be involved in apoptosis signaling pathway (BCL2L11), p53 pathway (PMAIP1, CDKN1A and FAS) and oxidative stress response (FDXR, CROT and JUN). Similarly, at 8 hours the genes with altered expression were involved in the apoptosis signaling pathway (BAX, BIK and JUN), p53 pathway (BAX, CDKN1A and FAS), oxidative stress response (FDXR and CROT) and p53 pathway feedback loops 2 (MDM2 and CDKN1A). A global molecular and biological interaction map analysis showed an association of these altered genes with apoptosis, senescence, DNA damage, oxidative stress, cell cycle arrest and caspase activation. In a targeted study, activation of apoptosis correlated with changes in gene expression of some of the above genes and revealed sequential activation of both intrinsic and extrinsic apoptotic pathways that precede ceramide accumulation and subsequent execution of apoptosis. One or more of these altered genes may be involved in p53-dependent ceramide accumulation.

Dataset Information

Enhanced pro-apoptosis gene signature following the activation of TAp63α in oocytes upon γ irradiation.

Publications

Enhanced pro-apoptosis gene signature following the activation of TAp63α in oocytes upon γ irradiation.

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