ArticleCell death & disease2020
The integrated stress response induces R-loops and hinders replication fork progression.
Article in Cell death & disease, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 14 citations in OpenAlex.
- Vitamin D3 ameliorates R-loop-induced replication stress and chromosomal instability in MED12-mutant uterine fibroids.Scientific reports · 2026Article
- Article
- Sortilin is Associated with PGRN-Mediated Endoplasmic Reticulum Stress and Activation of Microglia in a Rat Model of Degenerative Cervical Myelopathy.Neuromolecular medicine · 2026Article
- Vitamin D3 ameliorates R-loop-induced replication stress and chromosomal instability in MED12-mutant uterine fibroids.Research square · 2026Article
- APOBEC3C coordinates DDX5 in R-loop resolution and dynamic control of Chk1-mediated stress-responsive circuitry as a prerequisite for gemcitabine resistance in p53-deficient cells.Cell death & disease · 2026Article
- The role of dordaviprone in the multidisciplinary management of diffuse midline glioma.Surgical neurology international · 2026Review
- Proteasome and Ribosome Ubiquitination in Retinal Pigment Epithelial (RPE) Cells in Response to Oxidized Low-Density Lipoprotein (OxLDL).Biomedicines · 2025Article
- HPV induced R-loop formation represses innate immune gene expression while activating DNA damage repair pathways.PLoS pathogens · 2024Article
- A review of current therapeutics targeting the mitochondrial protease ClpP in diffuse midline glioma, H3 K27-altered.Neuro-oncology · 2024Review
- Hypoxia-induced transcriptional stress is mediated by ROS-induced R-loops.Nucleic acids research · 2023Article
- AATF/Che-1 localizes to paraspeckles and suppresses R-loops accumulation and interferon activation in Multiple Myeloma.The EMBO journal · 2022Article
- A genome-wide screen identifies SCAI as a modulator of the UV-induced replicative stress response.PLoS biology · 2022Article
- Aberrant R-loop-induced replication stress in MED12-mutant uterine fibroids.Scientific reports · 2022Article
- Pediatric glioblastoma cells are sensitive to drugs that inhibit eIF2α dephosphorylation and its phosphomimetic S51D variant.Frontiers in oncology · 2022Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The integrated stress response (ISR) allows cells to rapidly shutdown most of their protein synthesis in response to protein misfolding, amino acid deficiency, or virus infection. These stresses trigger the phosphorylation of the translation initiation factor eIF2alpha, which prevents the initiation of translation. Here we show that triggering the ISR drastically reduces the progression of DNA replication forks within 1 h, thus flanking the shutdown of protein synthesis with immediate inhibition of DNA synthesis. DNA replication is restored by compounds that inhibit eIF2alpha kinases or re-activate eIF2alpha. Mechanistically, the translational shutdown blocks histone synthesis, promoting the formation of DNA:RNA hybrids (R-loops), which interfere with DNA replication. R-loops accumulate upon histone depletion. Conversely, histone overexpression or R-loop removal by RNaseH1 each restores DNA replication in the context of ISR and histone depletion. In conclusion, the ISR rapidly stalls DNA synthesis through histone deficiency and R-loop formation. We propose that this shutdown mechanism prevents potentially detrimental DNA replication in the face of cellular stresses.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.