ADAR1 Links R-Loop Homeostasis to ATR Activation in Replication Stress Response
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ABSTRACT:
PROVIDER: PRJNA901169 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24884473_1.fastq.gz | Fastqsanger.gz | |||
| SRR24884473_2.fastq.gz | Fastqsanger.gz | |||
| SRR24884474_1.fastq.gz | Fastqsanger.gz | |||
| SRR24884474_2.fastq.gz | Fastqsanger.gz | |||
| SRR24884475_1.fastq.gz | Fastqsanger.gz |
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Project description:Unscheduled R-loops are a major source of replication stress and DNA damage. R-loop-induced replication defects are sensed and suppressed by ATR kinase, whereas it is not known whether R-loop itself is actively involved in ATR activation and, if so, how this is achieved. Here, we report that the nuclear form of RNA-editing enzyme ADAR1 promotes ATR activation and resolves genome-wide R-loops, a process that requires its double-stranded RNA-binding domains. Mechanistically, ADAR1 interacts with TOPBP1 and facilitates its loading on perturbed replication forks by enhancing the association of TOPBP1 with RAD9 of the 9-1-1 complex. When replication is inhibited, DNA-RNA hybrid competes with TOPBP1 for ADAR1 binding to promote the translocation of ADAR1 from damaged fork to R-loop region. There, ADAR1 recruits RNA helicases DHX9 and DDX21 to unwind R-loops, simultaneously allowing TOPBP1 to stimulate ATR more efficiently. Collectively, we propose that the tempo-spatially regulated assembly of ADAR1-nucleated protein complexes link R-loop clearance and ATR activation, while R-loops crosstalk with blocked replication forks by transposing ADAR1 to finetune ATR activity and safeguard the genome.
2023-09-01 | GSE217878 | GEO
Project description: Not available
| S-EPMC10681745 | biostudies-literature
Project description:As a part of the project looking into the role of ATR in regulating replication initiation, we report the replication timing analysis of the U2OS cells treated with ATR kinase inhibitor AZD6738
2019-07-26 | GSE131018 | GEO
Project description:as a part of the project looking into the role of ATR in regulating replication initiation and to investigate the rapid replication of CD8+ T cells, we report the replication timing analysis of murine CD8+ T cells and fibroblasts treated with ATR kinase inhibitor AZD6738
2022-05-01 | GSE183412 | GEO
Project description:RNA modification plays a crucial role in the regulation of various diseases and viral infections. ADAR1 (adenosine deaminase 1) is a key RNA editing enzyme that can convert adenosine (A) into the modified base inosine (I). This RNA modification has been confirmed to regulate the biological processes of various diseases and viruses. In our previous study on patients with thrombocytopenia syndrome, we conducted a longitudinal sampling study of transcriptomics and epigenetics (Nat. Commun., 2021, 12:5629). In this study, through the analysis of patient RNA-seq, we found that in patients infected with SFTSV, the expression of ADAR1 increased, and it gradually decreased with the recovery of the patients. By constructing cell models and conducting RNA sequencing analysis, we also obtained results similar to those from clinical samples. We found that ADAR1 knockdown promoted the replication of Bunyavirus (SFTSV), while overexpression inhibited virus replication. Further miRNA sequencing analysis revealed that after ADAR1 knockdown, some miRNAs with differential expression were produced, and the target genes of these differentially expressed miRNAs were closely related to neutrophil-mediated immune signaling pathways. These differentially expressed miRNAs may be due to ADAR1 editing the adenosine (A) in the double-stranded region of miRNA precursors to inosine (I), thereby changing the structure of dsRNA and making it difficult for Drosha or Dicer to obtain, thereby reducing the production of miRNAs. Considering these phenomena, we speculate that in the ADAR1 knockdown state, the changes in miRNA expression levels lead to the downregulation of genes involved in neutrophil-mediated immune signaling pathways, potentially causing neutrophil-mediated immune function impairment, thereby enhancing SFTSV replication. These findings provide new insights into the role of ADAR1 in SFTSV replication and immune signaling pathways, and provide a theoretical basis for the development of treatment strategies targeting ADAR1.
2026-01-07 | GSE286388 | GEO
Project description:DNA replication stress is the major cause of genomic instability in human cells. The ataxia telangiectasia and Rad3-related kinase (ATR) plays an essential role in the cellular response to replication stress and inhibition of ATR has emerged as therapeutic strategy for the treatment of cancer. However, the ATR-dependent signaling in the cellular response to replication stress has not been systematically investigated. Here, we employ quantitative mass spectrometry-based proteomics to decipher the ATR-dependent phosphorylation events in response to pathological replication stress induced by hydroxyurea. Our data define the substrate spectrum of ATR and identify several novel putative ATR substrates. In addition, we demonstrate that ATR-inhibition fundamentally rewires cellular signaling networks leading to the prominent activation of different pathways including the ATM-driven double strand break repair.
2017-03-29 | MSV000080795 | MassIVE
Project description:The ATR kinase, which coordinates cellular responses to DNA replication stress, is also essential for the proliferation of normal unstressed cells. Although its role in the replication stress response is well defined, the mechanisms by which ATR supports normal cell proliferation remain elusive. Here, we show that Atr is dispensable for the viability of G0-arrested naïve B cells. However, upon cytokine-induced proliferation, Atr-deficient B cells initiate DNA replication efficiently in early S phase, but by mid-S phase they display dNTP depletion, fork stalling, and replication failure. Nonetheless, productive DNA replication can be restored in Atr-deficient cells by pathways that suppress origin firing, such as downregulation of CDC7 and CDK1 kinase activities. Together, these findings indicate that ATR supports the proliferation of normal unstressed cells by tempering the pace of origin firing during the early S phase to avoid exhaustion of dNTPs and other replication factors.
2022-12-31 | GSE212195 | GEO
Project description:The ATR kinase, which coordinates cellular responses to DNA replication stress, is also essential for the proliferation of normal unstressed cells. Although its role in the replication stress response is well defined, the mechanisms by which ATR supports normal cell proliferation remain elusive. Here, we show that Atr is dispensable for the viability of G0-arrested naïve B cells. However, upon cytokine-induced proliferation, Atr-deficient B cells initiate DNA replication efficiently in early S phase, but by mid-S phase they display dNTP depletion, fork stalling, and replication failure. Nonetheless, productive DNA replication can be restored in Atr-deficient cells by pathways that suppress origin firing, such as downregulation of CDC7 and CDK1 kinase activities. Together, these findings indicate that ATR supports the proliferation of normal unstressed cells by tempering the pace of origin firing during the early S phase to avoid exhaustion of dNTPs and other replication factors.
2022-12-31 | GSE212194 | GEO
Project description:The ATR kinase, which coordinates cellular responses to DNA replication stress, is also essential for the proliferation of normal unstressed cells. Although its role in the replication stress response is well defined, the mechanisms by which ATR supports normal cell proliferation remain elusive. Here, we show that Atr is dispensable for the viability of G0-arrested naïve B cells. However, upon cytokine-induced proliferation, Atr-deficient B cells initiate DNA replication efficiently in early S phase, but by mid-S phase they display dNTP depletion, fork stalling, and replication failure. Nonetheless, productive DNA replication can be restored in Atr-deficient cells by pathways that suppress origin firing, such as downregulation of CDC7 and CDK1 kinase activities. Together, these findings indicate that ATR supports the proliferation of normal unstressed cells by tempering the pace of origin firing during the early S phase to avoid exhaustion of dNTPs and other replication factors.
2022-12-31 | GSE214643 | GEO
Project description:SLFN11 blocks stressed replication forks independently of ATR
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