ArticleGenes & development2008
TopBP1 activates ATR through ATRIP and a PIKK regulatory domain.
Article in Genes & development, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 230 papers.
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Who cites it
230 citing papers in PubMed, 359 citations in OpenAlex.
- An updated view on lagging strand DNA replication: implications for the replication stress response.Cell cycle (Georgetown, Tex.) · 2026Article
- DNA end-resection is stimulated by an interaction between BRCA1 exon 11 and TOPBP1.EMBO reports · 2026Article
- SPHINX31 acts as a SRPK1 inhibitor targeting the ATR/DNA-PKcs/CHK1 replicative checkpoint to inhibit cell growth in non-small cell lung cancer.Molecular oncology · 2026Article
- Mechanistic insights into phosphorylation-driven activation and therapeutic inhibition of human ATR-ATRIP.Nature structural & molecular biology · 2026Article
- Structural mechanism of TOPBP1 activating the ATR-ATRIP replication checkpoint kinase.Nature structural & molecular biology · 2026Article
- Review
- Tilting the balance of life and death: navigating DNA replication stress in cancer therapy.Experimental & molecular medicine · 2026Review
- Article
- Treacle-dependent TOPBP1 condensation regulates the nucleolar DNA damage response.Nucleic acids research · 2026Article
- TopBP1 orchestrates PU.1-IRF8 transcriptional programming of dendritic cell differentiation and Flt3L-driven tumor immunity.Experimental & molecular medicine · 2026Article
- Topoisomerase I inhibitor antibody-drug conjugates in breast cancer: the relevance of the DNA damage response to resistance, response, and combination treatment strategies.Breast cancer research and treatment · 2026Review
- β-tubulin phosphorylation by Chk1 is required for normal spindle formation during cell division.Communications biology · 2026Article
- RPA-independent activation of the ATR/CHK1 pathway.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Targeting ATR-CHK1 and ATM-CHK2 Axes in Pancreatic Cancer-A Comprehensive Review of Literature.International journal of molecular sciences · 2026Review
- REV7 associates with ATRIP and inhibits ATR kinase activity.Nucleic acids research · 2026Article
- CHK1 as a Metabolic and Immunological Regulator: Implications for Cancer Therapy.Oncology research · 2026Review
- Auranofin attenuates TOPBP1-mediated ATR replication stress response and improves chemotherapeutic response in breast tumor models.The Journal of clinical investigation · 2025Article
- Shining light on drug discovery: optogenetic screening for TopBP1 biomolecular condensate inhibitors.NAR cancer · 2025Article
- Therapeutic potential of PRMT1 as a critical survival dependency target in multiple myeloma.BMC cancer · 2025Article
- TopBP1 biomolecular condensates as a new therapeutic target in advanced-stage colorectal cancer.eLife · 2025Article
170 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The ATR (ATM and Rad3-related) kinase and its regulatory partner ATRIP (ATR-interacting protein) coordinate checkpoint responses to DNA damage and replication stress. TopBP1 functions as a general activator of ATR. However, the mechanism by which TopBP1 activates ATR is unknown. Here, we show that ATRIP contains a TopBP1-interacting region that is necessary for the association of TopBP1 and ATR, for TopBP1-mediated activation of ATR, and for cells to survive and recover DNA synthesis following replication stress. We demonstrate that this region is functionally conserved in the Saccharomyces cerevisiae ATRIP ortholog Ddc2, suggesting a conserved mechanism of regulation. In addition, we identify a domain of ATR that is critical for its activation by TopBP1. Mutations of the ATR PRD (PIKK [phosphoinositide 3-kinase related kinase] Regulatory Domain) do not affect the basal kinase activity of ATR but prevent its activation. Cellular complementation experiments demonstrate that TopBP1-mediated ATR activation is required for checkpoint signaling and cellular viability. The PRDs of ATM and mTOR (mammalian target of rapamycin) were shown previously to regulate the activities of these kinases, and our data indicate that the DNA-PKcs (DNA-dependent protein kinase catalytic subunit) PRD is important for DNA-PKcs regulation. Therefore, divergent amino acid sequences within the PRD and a unique protein partner allow each of these PIK kinases to respond to distinct cellular events.
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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.