Saccharomyces cerevisiae
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA108227 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:MOTIVATION: Fanconi anemia (FA) is a chromosomal instability syndrome originated by inherited mutations that impair the Fanconi Anemia/Breast Cancer (FA/BRCA) pathway, which is committed to the repair of DNA interstrand cross-links (ICLs). The disease displays increased spontaneous chromosomal aberrations and hypersensitivity to agents that create DNA interstrand cross-links. In spite of DNA damage, FA/BRCA-deficient cells are able to progress throughout the cell cycle, probably due to the activity of alternative DNA repair pathways, or due to defects in the checkpoints that monitor DNA integrity. RESULTS: We propose a Boolean network model of the FA/BRCA pathway, Checkpoint proteins and some alternative DNA repair pathways. To our knowledge, this is the largest network model incorporating a DNA repair pathway. Our model is able to simulate the ICL repair process mediated by the FA/BRCA pathway, the activation of Checkpoint proteins observed by recurrent DNA damage, as well as the repair of DNA double-strand breaks and DNA adducts. We generated a series of simulations for mutants, some of which have never been reported and thus constitute predictions about the function of the FA/BRCA pathway. Finally, our model suggests alternative DNA repair pathways that become active whenever the FA/BRCA pathway is defective.
| 1778 | Cell Collective
Project description:Oxidative DNA damage is likely to be involved in the etiology of cancer and is thought to accelerate tumorigenesis via increased mutation rates. However, the majority of malignant cells acquire a specific type of genomic instability characterized by large-scale genomic rearrangements, defined as chromosomal instability (CIN). The molecular mechanisms underlying CIN are largely unknown. We utilized Saccharomyces cerevisiae as a model system to delineate the relationship between genotoxic stress and CIN. It was found that elevated levels of chronic, unrepaired oxidative DNA damage cause chromosomal aberrations at remarkably high frequencies under both selective and non-selective growth conditions. In this system, exceeding the cellular capacity to appropriately manage oxidative DNA damage results in a “gain of CIN” phenotype and leads to profound karyotypic diversification. These results illustrate a novel mechanism for genome destabilization, which is likely to be relevant to human carcinogenesis. Keywords: CGH-array
2008-02-10 | GSE10152 | GEO
Project description:The ability to survive stress conditions is important for every living cell. Some stresses can affect not only current cell well-being, but may have far-reaching consequences. Uncurbed oxidative stress can cause DNA damage and the decrease in cell survival and/or increase in mutation rate. Some substances generating oxidative damage in the cell act mainly on DNA. Radiomimetic zeocin is a chemoenzyme that causes oxidative damage in DNA, inducing predominantly single or double strand breaks. Such lesions can subsequently lead to chromosomal rearrangements in genomic DNA, especially in diploid cells in which each sequence has its duplicate in the homologous chromosome. In a global screen for mutants oversensitive to zeocin, we selected 136 genes whose deletion causes the decrease in survival of diploid Saccharomyces cerevisiae cells exposed to this compound. The screen revealed numerous genes connected with stress response, including response to DNA damage stimulus; DNA repair genes, especially connected with homologous recombination and telomere maintenance; genes involved in cell cycle progression, chiefly in control of cell divisions checkpoints, both meiotic and mitotic; and genes involved in remodeling of chromatin. Notably, our screen also demonstrated the involvement of vesicular trafficking system in cell protection against DNA damage. Presented data imply vesicular system in various pathways of cell protection from zeocin-dependent damage, including the role in detoxification and probably more direct role in genome maintenance processes. We show, that cells with vesicular trafficking dysfunction are unable to repair zeocin induced damage, accumulate Rad52 foci and frequently possess an atypical DNA content. Therefore, we postulate that functional vesicular trafficking is crucial for sustaining integral genome. We believe that numerous new genes implicated in genome maintenance after genotoxic oxidative stress, together with newly discovered vesicular trafficking link to genome integrity, will help revealing novel molecular processes involved in the genome stability of diploid cells.
2015-03-16 | GSE59193 | GEO
Project description:Mastl is commonly overexpressed in cancer, appearing as an alternative therapeutic anticancer target. Loss of Mastl induces multiple chromosomal mitotic errors that lead to the accumulation of micronuclei and multilobulated cells with polyploidy. Our detailed analyses display that loss of Mastl quickly lead to chromosomes breakage and abnormalities impairing correct segregation. Phosphoproteomic data of mouse embryonic fibroblasts revealed defects in kinetochores, perichromosomes, and centrosomes but also on RNA binding proteins and double strand DNA damage repair.In our study, Rad51ap1, a well-known homologous recombination regulator, appeared to be effectively phosphorylated by Nek2 and CDK1, but also efficiently depshosphorylated by PP2A/B55. Taken together, these results suggest that Mastl loss induces a multitude of alteration even in noncancerous cells that lead to the disruption of DNA damage repair triggering chromosomes breakage and in consequence, creates an accumulative disequilibrium in the phosphoproteome.
2020-10-15 | PXD019297 | JPOST Repository
Project description:The Mre11 complex (Mre11, Rad50, and Nbs1) and Chk2 have been implicated in the DNA damage response, an inducible process required for the suppression of malignancy. The Mre11 complex is predominantly required for repair and checkpoint activation in S phase, while Chk2 governs apoptosis. We examined the relationship between the Mre11 complex and Chk2 in the DNA damage response via the establishment of Nbs1âB/âB Chk2-/- and Mre11ATLD1/ATLD1 Chk2-/- mice. Chk2 deficiency did not modify the checkpoint defects or chromosomal instability of Mre11 complex mutants; however, the double mutant mice exhibited synergistic defects in DNA damage-induced p53 regulation and apoptosis. Nbs1âB/âB Chk2-/- and Mre11ATLD1/ATLD1 Chk2-/- mice were also predisposed to tumors. In contrast, DNA-PKcs deficient mice, in which G1-specific chromosome breaks are present, did not exhibit synergy with Chk2-/- mutants. These data suggest that Chk2 suppresses the oncogenic potential of DNA damage arising during S and G2 phases of the cell cycle. Experiment Overall Design: Thymocytes from Wild type (Wt), Atm-/- and Chk2-/- mice were exposed to mock 5 Gy radiation (IR). The RNA was harvested 8 hours post treatment.
2008-06-20 | E-GEOD-11436 | biostudies-arrayexpress
Project description:Targetted metabolomics in U2OS PRDX1 WT and PRDX1-/- While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential when cells are exposed to DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Subsequent analysis identified Peroxiredoxin 1, PRDX1, as fundamental for DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it is required to reduce DNA damage-induced nuclear reactive oxygen species levels. Moreover, PRDX1 controls aspartate availability, which is required for the DNA damage repair-induced upregulation of de novo nucleotide synthesis. Loss of PRDX1 leads to an impairment in the clearance of γΗ2ΑΧ nuclear foci, accumulation of replicative stress and cell proliferation defects, thus revealing a crucial role for PRDX1 as a DNA damage surveillance factor.
2022-07-19 | ST002234 | MetabolomicsWorkbench
Project description:In the yeast Saccharomyces cerevisiae, cleavage factor I (CFI) and cleavage and polyadenylation factor (CPF) build the core of the transcription termination machinery. CFI comprises the Rna14, Rna15, Pcf11, and Clp1 proteins, as well as the associated Hrp5 RNA-binding protein. We found that CFI participates in the DNA damage response and that rna14-1 shows synthetic growth defects with mutants of different repair pathways, including homologous recombination, non-homologous end joining, post replicative repair, mismatch repair, and nucleotide excision repair, implicating that impaired RNAPII termination and 3â-end processing decreases the cellular tolerance for DNA damage. Beyond replication progression defects, we found that bypass of the G1/S checkpoint in rna14-1 cells leads to synthetic sickness, accumulation of phosphorylated H2A, as well as increase in Rad52-foci and in recombination. Our data provide evidence that CFI dysfunction impairs RNAPII turnover, leading to replication hindrance and lower tolerance to exogenous DNA damage. These findings underscore the importance of coordination between transcription termination, DNA repair and replication in the maintenance of genomic stability. S. cerevisiae strains were grown in YPAD liquid culture at 30°C, total RNA was isolated and hybridized on Affymetrix microarrays.
2014-03-31 | E-GEOD-50947 | biostudies-arrayexpress
Project description:The large majority of oxidative lesions occurring in the G1 phase of the cell cycle are repaired by base excision repair (BER) rather than mismatch repair (MMR) to avoid long resections that can lead to genomic instability and cell death. However, how cells choose BER over MMR is not yet understood. Here, we show that, during G1, D-type cyclins are recruited to sites of oxidative DNA damage in a PCNA- and p21-dependent manner. In turn, in a manner that is independent on CDK4/6 activity, D-type cyclins stabilize p21, which competes through its PCNA-interacting protein (PIP) box with MMR components for their binding to PCNA. This reduces MMR activity while allowing BER. At the G1/S transition, the AMBRA1-dependent degradation of D-type cyclins renders p21 susceptible to proteolysis via SKP2 and CDT2. These timely degradation events allow the proper binding of MMR proteins to PCNA enabling the repair of DNA replication errors. Thus, the expression of D-type cyclins limit MMR in G1, whereas their degradation is necessary for proper MMR function in S. Defects in these two regulatory mechanisms promote genome instability. The mass spectrometry raw files correspond to the affinity purifications of proximity labeled (turbo-ID) PCNA and CCND1 under various conditions.
2023-01-03 | MSV000091006 | MassIVE
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:Ataxia-telangiectasia (A-T) is a disease characterized by genomic instability and severe neurodegeneration. It is caused by mutation in Ataxia-telangiectasia mutated gene (ATM) which encodes ATM, a key player in DNA double-strand break (DSB) repair. While many major symptoms of A-T (including hypersensitivity to ionizing radiation) are readily explained by its deficiency in repair of DSBs, the causes for the devastating cerebellar degeneration are still elusive. Here we report that in A-T, persistent unrepaired DNA damage signals from the nucleus to mitochondria (NM signaling) causing mitochondrial dysfunction leading to neurodegeneration. We find that depletion of NAD+ in A-T across species is likely due to persistent PARylation as inhibition of PARP1 restores NAD+levels.. NAD+ depletion affects the NAD+/SIRT1-PGC1α axis causing accumulation of damaged mitochondria through inhibition of mitophagy. Restoration of NAD+/SIRT1 activity through PARP1 inhibition, NAD+ supplementation or SIRT1 activation rescued the pathological and behavioral defects in A-T, suggesting a conserved role of the NAD+/SIRT1 pathway in inhibiting disease pathology. Notably, increasing the NAD+ levels extends lifespan and rescues A-T-specific behavioral defects in both C. elegans and mouse models of A-T. This is through induction of PINK1-DCT1-regulated mitophagy and DNA-PKcs-associated NHEJ DNA repair. Our results underscore the unified role of SIRT1 (Sir2.1) in mitochondrial health and highlight how Sir2.1 not only regulates mitochondrial biogenesis, but also induces PINK1-DCT1-dependent mitophagy. Our data support a model where by the two major theories on aging, DNA damage accumulation and mitochondrial dysfunction, conspire to promote neurodegeneration in A-T animal models and suggest that therapeutic interventions are possible in A-T and other untreatable DNA repair-deficient disorders.
2018-06-25 | PXD003380 | Pride