ArticlePLoS genetics2013
An essential function for the ATR-activation-domain (AAD) of TopBP1 in mouse development and cellular senescence.
Article in PLoS genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 80 citations in OpenAlex.
- 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
- Structural mechanism of TOPBP1 activating the ATR-ATRIP replication checkpoint kinase.Nature structural & molecular biology · 2026Article
- Dpb11 facilitates the colocalization of Mec1-Ddc2 with its activators on gapped DNA.Cell reports · 2026Article
- Shining light on drug discovery: optogenetic screening for TopBP1 biomolecular condensate inhibitors.NAR cancer · 2025Article
- Molecular interplay between the DNA damage checkpoint kinase Mec1-Ddc2 and its activator Dpb11 on gapped DNA.bioRxiv : the preprint server for biology · 2025Article
- TopBP1 biomolecular condensates as a new therapeutic target in advanced-stage colorectal cancer.eLife · 2025Article
- Replication stress, microcephalic primordial dwarfism, and compromised immunity in ATRIP deficient patients.The Journal of experimental medicine · 2025Article
- The Potential for Targeting GCancers · 2024Review
- Advances in the mechanism of small nucleolar RNA and its role in DNA damage response.Military Medical Research · 2024Review
- Single-molecule imaging reveals the mechanism of bidirectional replication initiation in metazoa.Cell · 2024Article
- Single-Molecule Imaging Reveals the Mechanism of Bidirectional Replication Initiation in Metazoa.bioRxiv : the preprint server for biology · 2024Article
- A TOPBP1 allele causing male infertility uncouples XY silencing dynamics from sex body formation.eLife · 2024Article
- Poly(ADP-Ribose) Polymerase-1 Lacking Enzymatic Activity Is Not Compatible with Mouse Development.Cells · 2023Article
- Role of condensates in modulating DNA repair pathways and its implication for chemoresistance.The Journal of biological chemistry · 2023Review
- The Application of ATR Kinase Inhibitor AZD6738 in Combination with Radiotherapy for the Treatment of Melanoma.Journal of biomedical physics & engineering · 2022Article
- DNA damage responses that enhance resilience to replication stress.Cellular and molecular life sciences : CMLS · 2021Review
- Novel insights into the mechanism of cell cycle kinases Mec1(ATR) and Tel1(ATM).Critical reviews in biochemistry and molecular biology · 2021Article
- ATR regulates neuronal activity by modulating presynaptic firing.Nature communications · 2021Article
- PHF8-promoted TOPBP1 demethylation drives ATR activation and preserves genome stability.Science advances · 2021Article
- An Eye in the Replication Stress Response: Lessons From Tissue-Specific StudiesFrontiers in cell and developmental biology · 2021Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
ATR activation is dependent on temporal and spatial interactions with partner proteins. In the budding yeast model, three proteins - Dpb11(TopBP1), Ddc1(Rad9) and Dna2 - all interact with and activate Mec1(ATR). Each contains an ATR activation domain (ADD) that interacts directly with the Mec1(ATR):Ddc2(ATRIP) complex. Any of the Dpb11(TopBP1), Ddc1(Rad9) or Dna2 ADDs is sufficient to activate Mec1(ATR) in vitro. All three can also independently activate Mec1(ATR) in vivo: the checkpoint is lost only when all three AADs are absent. In metazoans, only TopBP1 has been identified as a direct ATR activator. Depletion-replacement approaches suggest the TopBP1-AAD is both sufficient and necessary for ATR activation. The physiological function of the TopBP1 AAD is, however, unknown. We created a knock-in point mutation (W1147R) that ablates mouse TopBP1-AAD function. TopBP1-W1147R is early embryonic lethal. To analyse TopBP1-W1147R cellular function in vivo, we silenced the wild type TopBP1 allele in heterozygous MEFs. AAD inactivation impaired cell proliferation, promoted premature senescence and compromised Chk1 signalling following UV irradiation. We also show enforced TopBP1 dimerization promotes ATR-dependent Chk1 phosphorylation. Our data suggest that, unlike the yeast models, the TopBP1-AAD is the major activator of ATR, sustaining cell proliferation and embryonic development.
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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.