ArticleCurrent biology : CB2013
Chk1 inhibits E2F6 repressor function in response to replication stress to maintain cell-cycle transcription.
Article in Current biology : CB, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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51 citing papers in PubMed, 77 citations in OpenAlex.
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- Single-cell transcriptomic dissection of two waves of endothelial-hematopoietic transition in a murine yolk sac.Blood science (Baltimore, Md.) · 2025Article
- Nrm1 is a bistable switch connecting cell cycle progression to transcriptional control.EMBO reports · 2025Article
- Clinical approaches to overcome PARP inhibitor resistance.Molecular cancer · 2025Review
- MiR-6837-3p protected retinal epithelial cells from oxidative stress by targeting E2F6.International ophthalmology · 2025Article
- Physiological and molecular mechanisms associated with potato tuber dormancy.Journal of experimental botany · 2024Review
- BOD1L mediates chromatin binding and non-canonical function of H3K4 methyltransferase SETD1A.Nucleic acids research · 2024Article
- Combined strategies with PARP inhibitors for the treatment of BRCA wide type cancer.Frontiers in oncology · 2024Review
- TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation.Nature communications · 2023Article
- Cellular Senescence in Acute and Chronic Wound Repair.Cold Spring Harbor perspectives in biology · 2022Review
- Atlas of regulated target genes of transcription factors (ART-TF) in human ES cells.BMC bioinformatics · 2022Article
- Cell cycle checkpoints and beyond: Exploiting the ATR/CHK1/WEE1 pathway for the treatment of PARP inhibitor-resistant cancer.Pharmacological research · 2022Review
- E2F6 initiates stable epigenetic silencing of germline genes during embryonic development.Nature communications · 2021Article
- E2F7 Is a Potent Inhibitor of Liver Tumor Growth in Adult Mice.Hepatology (Baltimore, Md.) · 2021Article
- E2F-dependent transcription determines replication capacity and S phase length.Nature communications · 2020Article
- Intrinsic ATR signaling shapes DNA end resection and suppresses toxic DNA-PKcs signaling.NAR cancer · 2020Article
- E2F1: Cause and Consequence of DNA Replication Stress.Frontiers in molecular biosciences · 2020Review
- Gcn5-mediated acetylation at MBF-regulated promoters induces the G1/S transcriptional wave.Nucleic acids research · 2019Article
- DNA damage kinase signaling: checkpoint and repair at 30 years.The EMBO journal · 2019Review
- Genome-Wide CRISPR-Cas9 Screening Identifies NF-κB/E2F6 Responsible for EGFRvIII-Associated Temozolomide Resistance in Glioblastoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2019Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundIn eukaryotic cells, detection of replication stress results in the activation of the DNA replication checkpoint, a signaling cascade whose central players are the kinases ATR and Chk1. The checkpoint response prevents the accumulation of DNA damage and ensures cell viability by delaying progression into mitosis. However, the role and mechanism of the replication checkpoint transcriptional response in human cells, which is p53 independent, is largely unknown.
resultsWe show that, in response to DNA replication stress, the regular E2F-dependent cell-cycle transcriptional program is maintained at high levels, and we establish the mechanisms governing such transcriptional upregulation. E2F6, a repressor of E2F-dependent G1/S transcription, replaces the activating E2Fs at promoters to repress transcription in cells progressing into S phase in unperturbed conditions. After replication stress, the checkpoint kinase Chk1 phosphorylates E2F6, leading to its dissociation from promoters. This promotes E2F-dependent transcription, which mediates cell survival by preventing DNA damage and cell death.
conclusionsThis work reveals, for the first time, that the regular cell-cycle transcriptional program is part of the DNA replication checkpoint response in human cells and establishes the molecular mechanism involved. We show that maintaining high levels of G1/S cell-cycle transcription in response to replication stress contributes to two key functions of the DNA replication checkpoint response, namely, preventing genomic instability and cell death. Given the critical role of replication stress in oncogene transformation, a detailed understanding of the molecular mechanisms involved in the checkpoint response will contribute to a better insight into cancer development.
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