Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1147155 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30207757_1.fastq.gz | Fastqsanger.gz | |||
| SRR30207757_2.fastq.gz | Fastqsanger.gz | |||
| SRR30207758_1.fastq.gz | Fastqsanger.gz | |||
| SRR30207758_2.fastq.gz | Fastqsanger.gz | |||
| SRR30207759_1.fastq.gz | Fastqsanger.gz |
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Project description:Mirror-image nucleosides, as potential antiviral drugs, can inhibit virus DNA polymerase to prevent virus replication. Conversely, they may be inserted into the DNA strands during DNA replication or transcription processes, leading to mutations that affect genome stability. Accumulation of significant mutation damage in cells may result in cell aging, apoptosis, and even uncontrolled cell division. We have previously explored replicative repair of mirror-image nucleosides within Escherichia coli, and this study focuses on human cells. We constructed several plasmid substrates, each carrying a specific mirror-image nucleoside, to investigate their impact on intracellular DNA replication and transcription processes. The results showed that in HepG2 cells, L-adenosine (L-dA) was the most potent substrate in inhibiting cell replication and transcription. L-cytidine (L-dC) exhibited the highest bypass efficiency in both template and non-template strands and had the most diverse mutation types. We also observed that L-dC induced immunoregulation of the JAK-STAT signaling pathway. Therefore, our results provide a theoretical basis for the disruptions caused by mirror-image nucleosides in replication and transcription and give us some understanding that mirror-image nucleoside drugs can cause cytotoxicity.
2024-08-13 | GSE274758 | GEO
Project description:Effects of mirror-image nucleosides on DNA replication and transcription in human cells
| PRJNA1147764 | ENA
Project description:The development of mirror-image biology systems and related applications is hindered by the lack of effective methods to sequence mirror-image (D-) proteins. Although natural-chirality (L-) proteins can be sequenced by bottom–up liquid chromatography–tandem mass spectrometry (LC–MS/MS), the sequencing of long D-peptides and D-proteins with the same strategy requires digestion by a site-specific D-protease before mass analysis. Here we apply solid-phase peptide synthesis and native chemical ligation to chemically synthesize a mirror-image version of trypsin, a widely used protease for site-specific protein digestion. Using mirror-image trypsin digestion and LC–MS/MS, we sequence a mirror-image large subunit ribosomal protein (L25) and a mirror-image Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4), and distinguish between different mutants of D-Dpo4. We also perform writing and reading of digital information in a long D-peptide of 50 amino acids. Thus, mirror-image trypsin digestion in conjunction with LC–MS/MS may facilitate practical applications of D-peptides and D-proteins as potential therapeutic and informational tools.
2024-01-19 | PXD046228 | Pride
Project description:Chromosomal instability in early cancer stages is caused by stress on DNA replication. The molecular basis for replication perturbation in this context is currently unknown. We studied the replication dynamics in cells in which a regulator of S-phase entry and cell proliferation, the Rb-E2F pathway, is aberrantly activated. Aberrant activation of this pathway by HPV-16 E6/E7 or cyclin E oncogenes, significantly decreased the cellular nucleotide levels in the newly transformed cells. Exogenously supplied nucleosides rescued the replication stress and DNA damage, and dramatically decreased oncogene-induced transformation. Increased transcription of nucleotide biosynthesis genes, mediated by expressing the transcription factor c-Myc, increased the nucleotide pool and also rescued the replication-induced DNA damage. Our results suggest a model for early oncogenesis in which uncoordinated activation of factors regulating cell proliferation leads to insufficient nucleotides that fail to support normal replication and genome stability. In order to understand the molecular basis for the low nucleotide pool in cells enforced to proliferate by oncogene expression, we performed unbiased whole transcriptome analysis of BJ cells in comparison to BJ cells expressing cyclin E, c-Myc and cells co-expressing both oncogenes. Our results suggest that Rb-E2F aberrant activation enforces cell proliferation but fails to activate the nucleotide biosynthesis pathway leading to insufficient pool of nucleotides required for normal replication. We analyzed two sets of BJ cells infected with empty pBabe, Cyclin E, c-Myc or coexpression of Cyclin E and c-Myc
2011-03-31 | E-GEOD-28266 | biostudies-arrayexpress
Project description:Transcription and replication conflict (TRC) are one of the main driving forces for genome instability. Yet, TRC rarely been discussed without the context of DNA:RNA entanglement, rending the role of transcription in other TRC unclear . In neural stem and progenitor cells, genes encode protein regulating neuron adhesion are hotspots for recurrent DNA break clusters (RDC). While RDC-containing genes are all actively transcribed, most RDC lack DNA:RNA entanglement. We demonstrated that, through controlled gain and loss of function genetic approaches, transcription activity is essential while not sufficient to induce RDC formation. In combination of a deep neural network and single-nucleotide resolution DNA break mapping approaches, we found RDC break densities mirror the replication fork dynamics. We demonstrated that, for the first time that, head-on TRC results in higher DNA break density than its co-direction counterparts. In summary, our results revealed that transcription has a higher-level regulatory role that has to be coordinated with DNA replication.
2024-03-18 | GSE233842 | GEO
Project description:Chromosomal instability in early cancer stages is caused by stress on DNA replication. The molecular basis for replication perturbation in this context is currently unknown. We studied the replication dynamics in cells in which a regulator of S-phase entry and cell proliferation, the Rb-E2F pathway, is aberrantly activated. Aberrant activation of this pathway by HPV-16 E6/E7 or cyclin E oncogenes, significantly decreased the cellular nucleotide levels in the newly transformed cells. Exogenously supplied nucleosides rescued the replication stress and DNA damage, and dramatically decreased oncogene-induced transformation. Increased transcription of nucleotide biosynthesis genes, mediated by expressing the transcription factor c-Myc, increased the nucleotide pool and also rescued the replication-induced DNA damage. Our results suggest a model for early oncogenesis in which uncoordinated activation of factors regulating cell proliferation leads to insufficient nucleotides that fail to support normal replication and genome stability. In order to understand the molecular basis for the low nucleotide pool in cells enforced to proliferate by oncogene expression, we performed unbiased whole transcriptome analysis of BJ cells in comparison to BJ cells expressing cyclin E, c-Myc and cells co-expressing both oncogenes. Our results suggest that Rb-E2F aberrant activation enforces cell proliferation but fails to activate the nucleotide biosynthesis pathway leading to insufficient pool of nucleotides required for normal replication.
2011-03-31 | GSE28266 | GEO
Project description:Cellular mechanisms that safeguard genome integrity are often subverted in cancer. To identify novel cancer-related genome caretakers, we employed a convergent multi-screening strategy coupled to quantitative image-based cytometry, and ranked candidate genes according to multivariate read-outs reflecting viability, proliferative capacity, replisome integrity and DNA damage signaling. This revealed new regulators of replication stress resilience, including components of the pre-mRNA cleavage and polyadenylation complex. We show that deregulation of pre-mRNA cleavage impairs replication fork speed and leads to excessive origin activity, rendering cells highly dependent on ATR kinase activity. Surprisingly, while excessive formation of RNA:DNA-hybrids under these conditions appears mainly as consequence rather than cause of DNA damage, inhibition of transcription rescued fork speed, origin activation and alleviated replication catastrophe. Importantly, uncoupling pre-mRNA processing from nuclear export by depleting the THO complex also protected cells from DNA damage, suggesting that efficient pre-mRNA cleavage provides a mechanism to prevent gene gating-associated genomic instability.
2019-01-10 | GSE118795 | GEO
Project description:Mirror-image proteins, composed of D-amino acids, are an attractive therapeutic modality, as they exhibit high metabolic stability and lack immunogenicity. Development of mirror-image binding proteins is achieved through chemical synthesis of D-target proteins, phage display library selection of L-binders and chemical synthesis of (mirror-image) D binders that consequently bind the physiological L-targets. Monobodies are well-established synthetic (L )binding proteins and their small size (~90 residues) and lack of endogenous cysteine residues make them particularly accessible to chemical synthesis. Here, we developed monobodies with nanomolar binding affinities against the D-SH2 domain of the leukemic tyrosine kinase BCR::ABL1. Two crystal structures of heterochiral monobody-SH2 complexes revealed targeting of the pY binding pocket by an unconventional binding mode. We then prepared potent D-monobodies by either ligating two chemically synthesized D-peptides or by self-assembly without ligation. Their proper folding and stability were determined and high affinity binding to the L-target was shown. D-monobodies were protease-resistant, showed long-term plasma stability, inhibited BCR::ABL1 kinase activity and bound BCR::ABL1 in cells and (to some extent in) cell lysates with high selectivity. Hence, we demonstrate that functional D monobodies can be developed readily. Our work represents an important step towards the possible future therapeutic use of D-monobodies when combined with emerging methods to enable cytoplasmic delivery of monobodies.
2024-10-28 | PXD056009 | Pride
Project description:We describe how the cancer-causing Epstein-Barr virus (EBV), a prototypic herpesvirus, alters proteome at viral replication forks prominently identifies chromatin modifying and transcriptional repression proteins. Specifically, to transition from transcription, the viral DNA polymerase processivity factor EA-D is SUMOylated by the transcriptional corepressor KAP1-TRIM28. KAP1 function is triggered by phosphorylation via the PI3K-related kinase ATM and the helicase RECQ5 at the transcription machinery. SUMO-EA-D recruits the histone loader CAF1 and the methyltransferase SETDB1 to silence the parental genome, prioritizing replication. Thus, DNA repair, epigenetic, and transcription-replication interference pathways orchestrate the handover from transcription to replication, a fundamental feature of DNA viruses
2023-02-27 | MSV000091375 | MassIVE
Project description:Interferon-β signaling has been shown to play important roles in anti-virus as well as anti-tumor immunity. We here report that the key transcription factor in type I interferon signaling, IRF3, as well as downstream interferon-β are able to induce replication stress signaling in triple-negative breast cancer cells. IRF3 overexpression sensitizes triple-negative breast cancer cells to several genotoxic agents. Addition of IFN-β, a key downstream cytokine of IRF3,reduced replication fork speed and activated ATR-CHK1 signaling. Conversely, type I interferon-neutralizing antibodies or nucleosides supplementation rescued IRF3-induced replication stress.
2024-05-01 | GSE263947 | GEO