telomere maintenance via telomere trimming / chromosomal region / telomeric 3' overhang formation / Mre11 complex / positive regulation of DNA catabolic process / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / blastocyst growth / positive regulation of DNA damage response, signal transduction by p53 class mediator / cellular response to nitrosative stress ...telomere maintenance via telomere trimming / chromosomal region / telomeric 3' overhang formation / Mre11 complex / positive regulation of DNA catabolic process / establishment of RNA localization to telomere / positive regulation of telomerase catalytic core complex assembly / blastocyst growth / positive regulation of DNA damage response, signal transduction by p53 class mediator / cellular response to nitrosative stress / establishment of protein-containing complex localization to telomere / regulation of microglial cell activation / negative regulation of telomere capping / protection from non-homologous end joining at telomere / Sensing of DNA Double Strand Breaks / BRCA1-C complex / positive regulation of telomere maintenance via telomere lengthening / telomere maintenance in response to DNA damage / R-loop processing / meiotic telomere clustering / phosphorylation-dependent protein binding / t-circle formation / DNA-dependent protein kinase activity / histone H2AXS139 kinase activity / male meiotic nuclear division / histone mRNA catabolic process / pre-B cell allelic exclusion / female meiotic nuclear division / chromatin-protein adaptor activity / pexophagy / DNA strand resection involved in replication fork processing / DNA double-strand break processing / cellular response to X-ray / regulation of telomere maintenance via telomerase / homologous recombination / nuclear inclusion body / peptidyl-serine autophosphorylation / lipoprotein catabolic process / V(D)J recombination / positive regulation of telomere maintenance / oocyte development / isotype switching / Impaired BRCA2 binding to PALB2 / protein localization to site of double-strand break / HDR through MMEJ (alt-NHEJ) / mitotic G2/M transition checkpoint / positive regulation of kinase activity / reciprocal meiotic recombination / DNA repair complex / Defective homologous recombination repair (HRR) due to BRCA1 loss of function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function / Homologous DNA Pairing and Strand Exchange / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / regulation of DNA-templated DNA replication initiation / DNA duplex unwinding / Resolution of D-loop Structures through Holliday Junction Intermediates / HDR through Single Strand Annealing (SSA) / Impaired BRCA2 binding to RAD51 / 1-phosphatidylinositol-3-kinase activity / response to ionizing radiation / mitotic spindle assembly checkpoint signaling / double-strand break repair via alternative nonhomologous end joining / TP53 Regulates Transcription of Caspase Activators and Caspases / negative regulation of B cell proliferation / mitotic G2 DNA damage checkpoint signaling / Presynaptic phase of homologous DNA pairing and strand exchange / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / peroxisomal matrix / protein K63-linked ubiquitination / neuromuscular process controlling balance / positive regulation of cell adhesion / positive regulation of double-strand break repair via homologous recombination / DNA damage response, signal transduction by p53 class mediator / replicative senescence / Regulation of HSF1-mediated heat shock response / neuroblast proliferation / signal transduction in response to DNA damage / somitogenesis / regulation of cellular response to heat / cellular response to retinoic acid / ovarian follicle development / positive regulation of protein autophosphorylation / negative regulation of TORC1 signaling / positive regulation of telomere maintenance via telomerase / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / Pexophagy / telomere maintenance / protein serine/threonine kinase activator activity / intrinsic apoptotic signaling pathway / post-embryonic development / thymus development / meiotic cell cycle / regulation of signal transduction by p53 class mediator / replication fork / DNA damage checkpoint signaling / regulation of autophagy / determination of adult lifespan / TP53 Regulates Transcription of DNA Repair Genes / Nonhomologous End-Joining (NHEJ) 類似検索 - 分子機能
Nibrin, C-terminal / Nibrin / DNA damage repair protein Nbs1 / DNA damage repair protein Nbs1 / Nibrin, second BRCT domain / Nibrin, second BRCT domain superfamily / Second BRCT domain on Nijmegen syndrome breakage protein / Nibrin-related / Telomere-length maintenance and DNA damage repair / Serine/threonine-protein kinase ATM, plant ...Nibrin, C-terminal / Nibrin / DNA damage repair protein Nbs1 / DNA damage repair protein Nbs1 / Nibrin, second BRCT domain / Nibrin, second BRCT domain superfamily / Second BRCT domain on Nijmegen syndrome breakage protein / Nibrin-related / Telomere-length maintenance and DNA damage repair / Serine/threonine-protein kinase ATM, plant / ATM, catalytic domain / Telomere-length maintenance and DNA damage repair / Telomere-length maintenance and DNA damage repair / FATC domain / PIK-related kinase, FAT / FAT domain / Forkhead associated domain / FATC / Forkhead-associated (FHA) domain profile. / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / FHA domain / Forkhead-associated (FHA) domain / SMAD/FHA domain superfamily / BRCA1 C Terminus (BRCT) domain / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / BRCT domain / BRCT domain superfamily / Armadillo-type fold / Protein kinase-like domain superfamily 類似検索 - ドメイン・相同性
National Institutes of Health/National Cancer Institute (NIH/NCI)
5F32CA247320
米国
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)
CA008748
米国
引用
ジャーナル: Elife / 年: 2022 タイトル: Structure of the human ATM kinase and mechanism of Nbs1 binding. 著者: Christopher Warren / Nikola P Pavletich / 要旨: 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, ...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.