ArticleThe Journal of biological chemistry2016
Probing the Mec1ATR Checkpoint Activation Mechanism with Small Peptides.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 20 citations in OpenAlex.
- Dpb11 facilitates the colocalization of Mec1-Ddc2 with its activators on gapped DNA.Cell reports · 2026Article
- Molecular interplay between the DNA damage checkpoint kinase Mec1-Ddc2 and its activator Dpb11 on gapped DNA.bioRxiv : the preprint server for biology · 2025Article
- DNA Damage and Replication Stress Checkpoints.Annual review of biochemistry · 2025Review
- Replication-IDentifier links epigenetic and metabolic pathways to the replication stress response.Nature communications · 2025Article
- Resection of DNA double-strand breaks activates Mre11-Rad50-Nbs1- and Rad9-Hus1-Rad1-dependent mechanisms that redundantly promote ATR checkpoint activation and end processing in Xenopus egg extracts.Nucleic acids research · 2024Article
- Novel insights into the mechanism of cell cycle kinases Mec1(ATR) and Tel1(ATM).Critical reviews in biochemistry and molecular biology · 2021Article
- Mechanism of auto-inhibition and activation of Mec1Nature structural & molecular biology · 2021Article
- Structural basis of homologous recombination.Cellular and molecular life sciences : CMLS · 2020Review
- Structural basis of allosteric regulation of Tel1/ATM kinase.Cell research · 2019Article
- Activation of Tel1The Journal of biological chemistry · 2019Article
- Common motifs in ETAA1 and TOPBP1 required for ATR kinase activation.The Journal of biological chemistry · 2019Article
- Separable roles for Mec1/ATR in genome maintenance, DNA replication, and checkpoint signaling.Genes & development · 2018Article
- Activation of the ATR kinase by the RPA-binding protein ETAA1.Nature cell biology · 2016Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 2 countries.
Funding
Abstract
Yeast Mec1, the ortholog of human ATR, is the apical protein kinase that initiates the cell cycle checkpoint in response to DNA damage and replication stress. The basal activity of Mec1 kinase is activated by cell cycle phase-specific activators. Three distinct activators stimulate Mec1 kinase using an intrinsically disordered domain of the protein. These are the Ddc1 subunit of the 9-1-1 checkpoint clamp (ortholog of human and Schizosaccharomyces pombe Rad9), the replication initiator Dpb11 (ortholog of human TopBP1 and S. pombe Cut5), and the multifunctional nuclease/helicase Dna2. Here, we use small peptides to determine the requirements for Mec1 activation. For Ddc1, we identify two essential aromatic amino acids in a hydrophobic environment that when fused together are proficient activators. Using this increased insight, we have been able to identify homologous motifs in S. pombe Rad9 that can activate Mec1. Furthermore, we show that a 9-amino acid Dna2-based peptide is sufficient for Mec1 activation. Studies with mutant activators suggest that binding of an activator to Mec1 is a two-step process, the first step involving the obligatory binding of essential aromatic amino acids to Mec1, followed by an enhancement in binding energy through interactions with neighboring sequences.
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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.