Role of lamin A in regulation of DNA Damage Response pathways in ovarian cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA870731 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21119108_1.fastq.gz | Fastqsanger.gz | |||
| SRR21119108_2.fastq.gz | Fastqsanger.gz | |||
| SRR21119109_1.fastq.gz | Fastqsanger.gz | |||
| SRR21119109_2.fastq.gz | Fastqsanger.gz | |||
| SRR21119110_1.fastq.gz | Fastqsanger.gz |
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Project description:A-type lamins, the key structural components of the nucleus, are emerging as regulators in the maintenance of nuclear architecture and genome organization. Extensive research for the last two decades has enormously contributed in understanding the roles of lamins in various signaling mechanisms which frequently go awry in neoplasias. It is interesting to know that alteration in lamin A/C expression and distribution drives tumorigenesis thus modifying its expression can be a potent therapeutic approach. One of the important signatures of a cancer cell is its inability to repair DNA damage which befalls due to a number of genomic defects that transform the cells to be sensitive to chemotherapeutic agents. Also, the errors in DNA repair mechanism are accompanied by high replication rate. This genomic and chromosomal instability is the most conventional feature found in cases of high grade ovarian serous carcinoma. Here, we report elevated levels of lamins in OVCAR3 cells (High grade ovarian serous carcinoma cell line) with respect to IOSE (Immortalised ovarian surface epithelial cells) and the altered damage repair machineries in both the cell lines. We have analysed the changes in global gene expression in sequel to DNA damage induced by etoposide in lamin A upregulated ovarian carcinoma background and reported a number of differentially expressed genes associated with pathways conferring cellular proliferation and chemoresistance. We highlight new avenues unravelling the role of an upregulated lamin A in confronting chemically induced genomic instability in the context of ovarian cancer.
2022-08-23 | GSE211529 | GEO
Project description:Embryonic stem cells (ESCs) which are susceptible to DNA damage depend on a robust and highly efficient DNA damage response (DDR) mechanism for their survival. However, the implications of physical force-mediated DNA damage on ESC fate remains unclear. Here we assessed the importance of DNA damage in ESC differentiation by culturing mouse ESCs (mESCs) on substrates of varying stiffness, which has been shown to induce stem cell differentiation. We show that stiffness-dependent mESC spreading induces DNA damage through nuclear compression that leads to loss of pluripotency, expression of Lamin A/C and germline markers. DNA damage and induction of Lamin A/C are observed in the presence of differentiating agents, as well as during mESC differentiation on cell derived matrices, identifying DNA damage as an early event in differentiation. Differentiation was also associated with reduction of DNA damage and activation of the DDR factor – ATR. While ATR is typically known to play roles in DDR pathway, its role during stiffness-mediated nuclear compression and mESC differentiation is unknown. Nuclear enrichment of activated ATR on stiff substrates and reduction of Lamin A/C expression due to ATR inhibition suggests that mESC differentiation is driven by nuclear compression-mediated DNA damage and involves ATR-dependent modulation of Lamin A/C.
2025-09-01 | GSE262150 | GEO
Project description:Down-regulation (DR) of PREP1 (aka PKNOX1) tumor suppressor induces H2Ax foci in human fibroblasts. Here we have analyzed the effect of PREP1 DR on DNA replication using cell cycle analysis, Repliseq, DNA combing, ChIP-seq, RNA-seq and immunofluorescence (IF). In human cells, PREP1 DR similarly affects both the rate of DNA replication and the progression of cells through the S phase. Genome wide, PREP1 DR induces late to early DNA replication shifts in normally late-replicated genomic regions amounting to 25% of the genome, in addition to unscheduled origins firing. A concomitant strong increase of unidirectional replication forks explains the appearance of DNA damage foci. The DNA target of PREP1 DR is the Lamin Associated DNA, in agreement with the simultaneous decrease of Lamin B1. Therefore PREP1 is a novel regulator of replication timing and Lamin B1 level, which ChIP-seq and RNA-seq data indicate as independent from its transcriptional activity. This activity must constitute the basis for its tumor suppression function.
2018-02-28 | GSE101774 | GEO
Project description:Down-regulation (DR) of PREP1 (aka PKNOX1) tumor suppressor induces H2Ax foci in human fibroblasts. Here we have analyzed the effect of PREP1 DR on DNA replication using cell cycle analysis, Repliseq, DNA combing, ChIP-seq, RNA-seq and immunofluorescence (IF). In human cells, PREP1 DR similarly affects both the rate of DNA replication and the progression of cells through the S phase. Genome wide, PREP1 DR induces late to early DNA replication shifts in normally late-replicated genomic regions amounting to 25% of the genome, in addition to unscheduled origins firing. A concomitant strong increase of unidirectional replication forks explains the appearance of DNA damage foci. The DNA target of PREP1 DR is the Lamin Associated DNA, in agreement with the simultaneous decrease of Lamin B1. Therefore PREP1 is a novel regulator of replication timing and Lamin B1 level, which ChIP-seq and RNA-seq data indicate as independent from its transcriptional activity. This activity must constitute the basis for its tumor suppression function.
2018-02-28 | GSE101773 | GEO
Project description:Down-regulation (DR) of PREP1 (aka PKNOX1) tumor suppressor induces H2Ax foci in human fibroblasts. Here we have analyzed the effect of PREP1 DR on DNA replication using cell cycle analysis, Repliseq, DNA combing, ChIP-seq, RNA-seq and immunofluorescence (IF). In human cells, PREP1 DR similarly affects both the rate of DNA replication and the progression of cells through the S phase. Genome wide, PREP1 DR induces late to early DNA replication shifts in normally late-replicated genomic regions amounting to 25% of the genome, in addition to unscheduled origins firing. A concomitant strong increase of unidirectional replication forks explains the appearance of DNA damage foci. The DNA target of PREP1 DR is the Lamin Associated DNA, in agreement with the simultaneous decrease of Lamin B1. Therefore PREP1 is a novel regulator of replication timing and Lamin B1 level, which ChIP-seq and RNA-seq data indicate as independent from its transcriptional activity. This activity must constitute the basis for its tumor suppression function.
2018-02-28 | GSE101775 | GEO
Project description:Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease, which ultimately results in heart failure (HF). Pathological genetic variants in LMNA cause DCM, which currently lacks specific treatment. Perturbing candidates related to dysregulated pathways have shown to ameliorate LMNA DCM, but their long-term efficacy as potential therapeutic targets is unknown. Here, we evaluated 14 potential candidates including Lmna gene products, key signaling pathways, calcium handling, proliferation regulators and Lamin interacting proteins, in a cardiac-specific Lmna DCM model. The candidates with improved cardiac function were further assessed through survival analysis. After comparing cardiac function, marker gene expression, Tgfβ signaling pathway activation, fibrosis, inflammation, proliferation, and DNA damage, we uncovered that restored cardiac function significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in Lmna DCM. Interestingly, Lamin C or Sun1 shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. In addition to Sun1 shRNA, perturbing the interaction between the nucleoskeleton and cytoskeleton via the KASH domain of Nesprin1 also effectively suppressed Lmna DCM. In contrast, Lamin A supplementation did not rescue long term survival and may impart a detrimental cardiotoxicity risk. Furthermore, transcriptome profiling was used to compare the differences between Lamin A and Lamin C treatment. Mechanistically, we identified that this lapse was attributed to a dose-dependent toxicity of Lamin A, which was independent of its maturation. This study highlights the potential for advancing Lamin C and Sun1 as therapeutic targets for the treatment of LMNA DCM.
2024-08-11 | GSE240745 | GEO
Project description:In order to evaluate pathways that drive the development of ovarian cancer, we compared Affymetrix expression profiles from normal ovarian surface epithelium to those from primary ovarian carcinomas. mRNA expression profiles for 57 ovarian carcinomas and 12 ovarian normal samples.
2015-06-22 | E-GEOD-66957 | biostudies-arrayexpress
Project description:In order to evaluate pathways that drive the development of ovarian cancer, we compared Affymetrix expression profiles from normal ovarian surface epithelium to those from primary ovarian carcinomas.
2015-06-22 | GSE66957 | GEO
Project description:influence of lamin B rereceptor knockout and lamin A/C knockout on gene expression in cultured myoblast cells and in striated muscle tissue knockout samples are obtained by mating of heterozygous animals. Homozygous KO and wt animals of one litter are compared. Two boilogical replicates of KO samples are processed in parallel. wt samples are used as controls. One wt sample is processed per KO litter. Where appropriate two wt samples are used as biological replicates.
2013-01-28 | E-GEOD-37076 | biostudies-arrayexpress
Project description:The integrity of the nuclear envelope (NE) is essential to maintain the structural stability of the nucleus. Rupture of the NE has been frequently observed in cancer cells, especially in the context of mechanical challenges, such as physical confinement and migration. However, spontaneous NE rupture events have also been described, without any obvious physical challenges to the cell. The molecular mechanism(s) of these spontaneous NE rupture events remain to be explored. Here, we show that DNA damage and subsequent ATR activation can lead to NE rupture. Upon DNA damage, Lamin A/C is phosphorylated in an ATR-dependent manner, leading to changes in lamina assembly and, ultimately, NE rupture. In addition, we show that cancer cells with intrinsic DNA repair defects undergo frequent events of DNA damage-induced NE rupture, which renders them extremely sensitive to further NE perturbations. Exploiting this NE vulnerability could provide a new angle to complement traditional, DNA damage-based chemotherapy.
2023-10-09 | PXD040857 | Pride