ArticleeLife2022
Structure of the human ATM kinase and mechanism of Nbs1 binding.
Article in eLife, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 53 citations in OpenAlex.
- DNA Repair Mechanisms.Methods in molecular biology (Clifton, N.J.) · 2027Review
- CRISPR Screening Identifies SMARCAL1 and MRN as Modulators of WRN Dependency in MSI-H Colorectal Cancer.Cancer research · 2026Article
- The Landscape of BRCA1-Associated Post-Translational Modifications.Cell biology international · 2026Review
- ATM immunohistochemistry as an effective screening method for POLE variants among endometrial carcinomas lacking mismatch repair deficiency and p53 abnormalities.The journal of pathology. Clinical research · 2026Article
- Analysis of Transcriptome and Differentially Expressed Genes in Chicken Primordial Germ Cells.Animals : an open access journal from MDPI · 2026Article
- G-quadruplex structures are key regulators of mammalian spermatogenesis.Cellular & molecular biology letters · 2026Article
- Structural pharmacogenomics of drug-associated SNPs in oral squamous cell carcinoma.Frontiers in genetics · 2026Article
- Crosstalk between chromatin state and ATM signalling in DNA damage-induced transcription stress.The EMBO journal · 2025Article
- Structural basis for DNA break sensing by human MRE11-RAD50-NBS1 and its regulation by telomeric factor TRF2.Nature communications · 2025Article
- Reclassification of ATM Missense Variants of Uncertain Significance by Integrating Results from Systematic Functional Assays into an ACMG Points-Based Framework.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- DNA Damage and Replication Stress Checkpoints.Annual review of biochemistry · 2025Review
- The Development of ATM Inhibitors in Cancer Therapy.Targeted oncology · 2025Review
- Molecular mechanisms of extrachromosomal circular DNA formation.Nucleic acids research · 2025Review
- Phosphorylated BLM peptide acts as an agonist for DNA damage response.Nucleic acids research · 2025Article
- Bioinformatic Analysis and Molecular Docking Identify Isorhamnetin Is a Candidate Compound in the Treatment of Pulmonary Artery Hypertension.Anatolian journal of cardiology · 2025Article
- Manganese mediates antiviral effects by driving an ATM -TBK1 phosphorylation signaling pathway.Frontiers in immunology · 2025Article
- Making PI3K superfamily enzymes run faster.Advances in biological regulation · 2025Review
- Cancer, metastasis, and the epigenome.Molecular cancer · 2024Review
- Germline mutations of breast cancer susceptibility genes through expanded genetic analysis in unselected Colombian patients.Human genomics · 2024Article
- DNA Double Strand Break and Response Fluorescent Assays: Choices and Interpretation.International journal of molecular sciences · 2024Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
DNA double-strand breaks (DSBs) can lead to mutations, chromosomal rearrangements, genome instability, and cancer. Central to the sensing of DSBs is the ATM (Ataxia-telangiectasia mutated) kinase, which belongs to the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family. In response to DSBs, ATM is activated by the MRN (Mre11-Rad50-Nbs1) protein complex through a poorly understood process that also requires double-stranded DNA. Previous studies indicate that the FxF/Y motif of Nbs1 directly binds to ATM, and is required to retain active ATM at sites of DNA damage. Here, we report the 2.5 Å resolution cryo-EM structures of human ATM and its complex with the Nbs1 FxF/Y motif. In keeping with previous structures of ATM and its yeast homolog Tel1, the dimeric human ATM kinase adopts a symmetric, butterfly-shaped structure. The conformation of the ATM kinase domain is most similar to the inactive states of other PIKKs, suggesting that activation may involve an analogous realigning of the N and C lobes along with relieving the blockage of the substrate-binding site. We also show that the Nbs1 FxF/Y motif binds to a conserved hydrophobic cleft within the Spiral domain of ATM, suggesting an allosteric mechanism of activation. We evaluate the importance of these structural findings with mutagenesis and biochemical assays.
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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.