{"gene":"NBN","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2006,"finding":"Drosophila Nbs mediates nuclear transport of the Mre11/Rad50 complex: Rad50 accumulates in nuclei of wild-type cells but not in nbs mutant cells, indicating Nbs is required for nuclear localization of the MRN complex. Epistasis analysis showed nbs functions in both ATM- and ATR-controlled telomere protection pathways, while all three MRN components function in a single pathway for DNA-damage-induced chromosome break repair.","method":"Genetic epistasis analysis in Drosophila nbs mutants; immunofluorescence/fractionation showing Rad50 nuclear localization; double-mutant analysis with tefu (ATM) and mei-41 (ATR)","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence, epistasis in multiple double-mutant backgrounds, single lab but multiple orthogonal methods","pmids":["16648644"],"is_preprint":false},{"year":2009,"finding":"In the nervous system, NBS1 (Nbs1) is required for normal ATM-dependent apoptosis after DNA damage: Nbs1ΔB/ΔB neural tissue shows defective ATM phosphorylation yet normal apoptosis, whereas Mre11ATLD1/ATLD1 tissue shows defective ATM activation and pronounced resistance to apoptosis. Genetic rescue experiments showed Mre11 and ATM backgrounds (but not Nbs1ΔB) rescue Lig4-induced microcephaly, placing Nbs1 and Mre11 in distinct sub-pathways for neural ATM signaling.","method":"Mouse conditional genetics; epistasis (Lig4 loss on Nbs1ΔB, Mre11ATLD1, Atm−/− backgrounds); immunoblotting for ATM substrates (Chk2, p53 phosphorylation); TUNEL apoptosis assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic epistasis experiments, defined phosphorylation readouts, replicated across multiple mutant backgrounds in a single rigorous study","pmids":["19171781"],"is_preprint":false},{"year":2012,"finding":"ATM phosphorylation of NBN regulates the kinetics of NBN and ATM accumulation at DNA double-strand break sites: phospho-blocking (Ser→Ala) mutations delayed recruitment of both NBN and ATM to DSBs, while phosphomimetic (Ser→Glu) substitutions increased and prolonged their accumulation. Full-length NBN was required for timely DSB repair.","method":"Direct protein transduction of site-specific endonuclease I-PpoI into isogenic cell lines expressing NBN phosphorylation mutants; chromatin immunoprecipitation at defined DSB sites; DSB repair kinetics assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-specific DSB system with isogenic phosphorylation mutant cell lines, ChIP quantification, and DSB repair assays; multiple orthogonal methods in one study","pmids":["23146902"],"is_preprint":false},{"year":2002,"finding":"After ionizing radiation, PML nuclear bodies associate with the hMre11/Rad50/NBS1 complex at sites of DNA double-strand breaks (marked by γ-H2AX), and ionizing radiation induces stable physical association of p53 with hMre11 and PML within these foci.","method":"Immunofluorescence co-localization with anti-γ-H2AX; co-immunoprecipitation of p53 with hMre11 and PML after IR in normal human fibroblasts","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and immunofluorescence co-localization, single lab, two orthogonal methods","pmids":["11896594"],"is_preprint":false},{"year":2017,"finding":"NBN (nibrin) and ATM are clients of the molecular chaperone Hsp90α: inhibition of Hsp90α ATPase activity with 17-AAG causes polyubiquitination and proteasomal degradation of ATM and NBN (but not 53BP1, RAD50, or MRE11). Hsp90α–ATM and Hsp90α–NBN complexes exist in unstressed and irradiated cells. Upon IR-induced DSBs, ATM phosphorylates NBN, which then dissociates from Hsp90α and translocates to DSB sites. Hsp90α inhibition impairs nuclear localization of MRE11 and RAD50, attenuates DDR signaling (BRCA1, CHK2 phosphorylation), and slows DSB repair.","method":"Co-immunoprecipitation of Hsp90α with ATM and NBN; 17-AAG inhibitor treatment with proteasome inhibitor rescue; immunofluorescence for MRE11/RAD50 nuclear localization; immunoblotting for phospho-NBN, phospho-BRCA1, phospho-CHK2; subcellular fractionation","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, pharmacological inhibition with rescue, multiple phosphorylation readouts, localization experiments with functional consequence, single lab but multiple orthogonal methods","pmids":["28631426"],"is_preprint":false},{"year":2014,"finding":"Full-length NBN protein interacts with a broad set of partners involved in DNA damage response, ROS scavenging, and protein folding. The 26 kDa fragment (p26, containing FHA/BRCT1 domains) arising from the NBS founder mutation 657del5 interacts with PARP1 after irradiation, and this interaction inhibits PARP1 activity (measured by NAD+ levels) and is associated with persistence of ROS and DSBs at 24 h post-IR.","method":"Affinity chromatography from transiently transfected HEK293 cells expressing full-length NBN, p26, or p70; SDS-PAGE separation and shotgun MS/MS protein identification; co-immunoprecipitation of p26 with PARP1; NAD+ assay for PARP1 activity","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — proteomics interactome plus co-IP and enzymatic activity assay for PARP1 inhibition by p26; single lab, two orthogonal methods for the PARP1 finding","pmids":["25485873"],"is_preprint":false},{"year":2010,"finding":"NBN (nibrin) is required for cellular resistance to O6-methylguanine-inducing agents (e.g., temozolomide, MNNG): NBN-mutant NBS cells are hypersensitive to these agents through increased apoptosis and necrosis. MGMT over-expression abrogated the hypersensitivity, indicating the response is specifically triggered by O6-methylguanine lesions requiring DSB processing by the MRN complex. siRNA knockdown of NBN in melanoma cells recapitulated the temozolomide sensitization.","method":"Clonogenic survival and cell death assays in NBN-mutant patient fibroblasts and lymphoblastoid cells; MGMT expression rescue experiment; siRNA knockdown of NBN in melanoma cells followed by temozolomide treatment; apoptosis/necrosis quantification","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function (patient cells + siRNA knockdown), MGMT rescue epistasis defining the responsible lesion type, multiple cell line systems, single lab but multiple orthogonal approaches","pmids":["20729302"],"is_preprint":false},{"year":2019,"finding":"Physical interaction between Nbn and the Mre11-Rad50 core is required for tumor suppression and normal hematopoiesis: a mouse Nbn allele (Nbnmid8) with severely impaired Mre11 binding caused profound hematopoietic defects, B cell development blockage, and rapid T cell leukemia. Leukemias showed focal amplification of 9qA2 causing MRE11 overexpression, interpreted as compensation for the weakened Mre11-Nbn interaction.","method":"Mouse genetics (conditional hematopoietic expression of Nbnmid8); flow cytometry of thymus and bone marrow cellularity; genomic analysis of tumors; copy number and gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — defined binding-impaired mutant allele in vivo with clear hematopoietic and tumor phenotype readout, genomic analysis of compensatory amplification; single lab with multiple orthogonal methods","pmids":["31285322"],"is_preprint":false},{"year":2019,"finding":"NBN variants causing isolated infertility produce an alternative p84-NBN protein (from in-frame exon 4-5 skipping) that retains the FHA domain but shows dramatically reduced protein levels and causes relocalization of the MRN complex from the nucleus to the cytoplasm. ATM also shifts from nucleus to cytoplasm in these cells, suggesting steady-state ATM–MRN nuclear co-localization depends on NBN. ATM pathway activation was partially preserved, and cell cycle checkpoint defects were milder than in typical NBS.","method":"Transcript analysis (RT-PCR, sequencing); immunoblotting for NBN protein variants; immunofluorescence for subcellular localization of MRN complex and ATM; ATM pathway activation assay (camptothecin treatment); cell cycle checkpoint analysis","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization experiments with functional consequence, multiple orthogonal methods, single lab","pmids":["31729086"],"is_preprint":false},{"year":2013,"finding":"The MRN complex (MRE11/RAD50/NBN) functions as a DNA double-strand break sensor and initiates DNA repair by activating ATM kinase, which coordinates repair with p53-dependent cell cycle checkpoint arrest. NBN contributes the FHA and BRCT domains for interaction with phosphorylated substrates and acts as the adapter subunit linking the MRE11 nuclease/RAD50 ATPase core to downstream checkpoint signaling.","method":"Review synthesizing functional genetic and biochemical studies (co-immunoprecipitation, domain deletion analyses, patient cell studies cited across the field)","journal":"Current genomics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — review paper summarizing published functional data without presenting new primary experiments","pmids":["24396275"],"is_preprint":false},{"year":2023,"finding":"Two novel NBN truncating variants (p.L19* and p.N71fs) produce a 45 kDa alternative-translation fragment that maintains binding to MRE11. Cells expressing these fragments show higher sensitivity to γ-irradiation and lower levels of radiation-induced KAP1 phosphorylation, indicating impaired ATM-dependent DDR signaling.","method":"Immunoblotting for alternative translation product; co-immunoprecipitation of 45 kDa fragment with MRE11; γ-irradiation survival assay; immunoblotting for phospho-KAP1","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP identifying MRE11 binding, functional readouts (radiation sensitivity + KAP1 phosphorylation), single lab, limited replication","pmids":["36346689"],"is_preprint":false},{"year":2014,"finding":"The NBN p.R215W missense mutation in the hemizygous state impairs NBN protein levels and abolishes formation of NBN foci at DNA damage sites after irradiation. Cells are highly radiosensitive, show impaired γH2AX, MDC1, and 53BP1 focus formation, and are hypersensitive to PARP1 inhibition, consistent with a combined NBN/BRCA1 deficiency. ATM signaling was largely unaffected despite NBN focus deficiency.","method":"Immunocytochemistry for NBN, γH2AX, MDC1, 53BP1 foci after IR; immunoblotting for NBN protein; clonogenic radiosensitivity assay; flow cytometry for cell cycle; impedance measurement for PARP1 inhibitor sensitivity","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in a naturally occurring cancer cell line with defined mutation, single lab","pmids":["24928521"],"is_preprint":false},{"year":2009,"finding":"Nibrin-deficient mouse cells show increased production of reactive oxygen species following induction of DSBs, implicating NBN in oxidative stress regulation in addition to DSB repair. Proteomic analysis revealed significant alterations in proteins involved in oxidative stress and cellular redox homeostasis in nibrin null mutant mice.","method":"Conditional null mutant mouse model; 2D-gel proteomics (~8,000 proteins resolved); ROS measurement in Nbn null mutant fibroblasts after DSB induction","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse knockout with proteomics and direct ROS measurement, single lab, two orthogonal methods","pmids":["19412544"],"is_preprint":false},{"year":2013,"finding":"Nbn gene inactivation in the CNS leads to defective proliferation and enhanced apoptosis of oligodendrocyte precursor cells (OPCs) causing hypomyelination of corpus callosum. ATM-Chk2 signaling drives apoptosis while AKT/mTOR signaling controls proliferation of Nbn-deficient OPCs; BDNF/NGF stimulation attenuates oxidative stress and restores OPC proliferation via AKT/mTOR/P70S6K.","method":"Nestin-Cre conditional Nbn knockout mouse; immunohistochemistry/immunofluorescence for myelin and OPC markers; immunoblotting for ATM-Chk2 and AKT/mTOR pathway components; BDNF/NGF rescue experiments","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional CNS knockout with defined pathway analysis and rescue experiments; single lab, multiple orthogonal methods","pmids":["24272991"],"is_preprint":false}],"current_model":"NBN (nibrin) functions as the adapter subunit of the MRE11/RAD50/NBN (MRN) complex, where it mediates nuclear import of MRE11-RAD50, recruits the complex to DNA double-strand break (DSB) sites through its FHA/BRCT domains, and facilitates ATM kinase activation; ATM in turn phosphorylates NBN to regulate the kinetics of MRN and ATM accumulation at DSBs, promote S-phase checkpoint signaling, and enable timely DSB repair, with NBN also functioning as an Hsp90α client protein whose chaperone-dependent stability is required for proper DDR signaling."},"narrative":{"mechanistic_narrative":"NBN (nibrin) is the adapter subunit of the MRE11/RAD50/NBN (MRN) complex, the sensor that detects DNA double-strand breaks (DSBs) and couples their repair to ATM-dependent checkpoint signaling [PMID:24396275]. NBN is required for nuclear import of the MRE11-RAD50 core: loss of nibrin function leaves Rad50 cytoplasmic, and NBN-mutant alleles that reduce protein levels or disrupt the steady-state association redistribute both MRN and ATM from nucleus to cytoplasm [PMID:16648644, PMID:31729086]. The physical NBN–MRE11 interaction is itself essential, as an allele with impaired Mre11 binding causes hematopoietic failure and T cell leukemia driven by compensatory MRE11 amplification [PMID:31285322]. At breaks, ATM phosphorylates NBN to set the kinetics of MRN and ATM accumulation at DSB sites and enable timely repair: phospho-blocking mutations delay recruitment while phosphomimetic substitutions prolong it [PMID:23146902]. NBN-mediated DSB processing is also required to resolve O6-methylguanine-derived lesions, since MGMT overexpression abolishes the temozolomide hypersensitivity of NBN-deficient cells [PMID:20729302]. Beyond canonical repair, nibrin restrains reactive-oxygen-species production after DSB induction [PMID:19412544] and, in the developing CNS, governs oligodendrocyte precursor survival and proliferation through ATM-Chk2 and AKT/mTOR signaling, with its loss producing hypomyelination [PMID:24272991]. NBN stability depends on the chaperone Hsp90α: pharmacological Hsp90α inhibition triggers polyubiquitination and proteasomal degradation of NBN and ATM, impairs MRE11/RAD50 nuclear localization, and attenuates downstream BRCA1 and CHK2 phosphorylation [PMID:28631426]. Patient-derived truncating and missense variants that abolish NBN focus formation or reduce protein levels confer radiosensitivity, impaired downstream focus formation, and PARP-inhibitor hypersensitivity [PMID:36346689, PMID:24928521].","teleology":[{"year":2002,"claim":"Established that the MRN complex physically organizes into DSB-associated nuclear structures together with PML and p53, linking MRN to checkpoint factors at damage sites.","evidence":"Immunofluorescence co-localization with γ-H2AX and co-IP of p53 with hMre11/PML after IR in human fibroblasts","pmids":["11896594"],"confidence":"Medium","gaps":["Does not define NBN's specific contribution to PML/p53 recruitment","Co-localization does not establish direct NBN binding to p53 or PML"]},{"year":2006,"claim":"Resolved that nibrin is required for nuclear import of the MRE11-RAD50 core, defining NBN's role as the adapter delivering the complex into the nucleus.","evidence":"Genetic epistasis and Rad50 localization in Drosophila nbs mutants with ATM/ATR double-mutant analysis","pmids":["16648644"],"confidence":"High","gaps":["Mechanism of NBN-mediated nuclear import (NLS usage, import machinery) not defined","Drosophila ortholog may not fully recapitulate human domain functions"]},{"year":2009,"claim":"Distinguished NBN from MRE11 in tissue-specific ATM signaling and revealed an unanticipated role for nibrin in restraining oxidative stress alongside DSB repair.","evidence":"Mouse conditional/null genetics with ATM-substrate immunoblotting and TUNEL; 2D-gel proteomics and ROS measurement in Nbn-null fibroblasts","pmids":["19171781","19412544"],"confidence":"High","gaps":["Molecular basis of NBN's ROS regulation not identified","Whether oxidative phenotype is a direct NBN function or downstream of unrepaired DSBs unresolved"]},{"year":2010,"claim":"Showed that MRN-dependent DSB processing is the basis of cellular resistance to O6-methylguanine lesions, defining a specific lesion type whose repair requires NBN.","evidence":"Clonogenic and cell-death assays in NBN-mutant patient cells and melanoma siRNA knockdown with MGMT rescue epistasis","pmids":["20729302"],"confidence":"High","gaps":["Step at which NBN acts on O6-methylguanine-derived DSBs not defined","Does not separate MRN nuclease activity from NBN adapter function"]},{"year":2012,"claim":"Demonstrated that ATM phosphorylation of NBN feeds back to control the kinetics of MRN and ATM accumulation at breaks, establishing NBN phosphorylation as a timing regulator of the DDR.","evidence":"Site-specific I-PpoI endonuclease in isogenic NBN phospho-mutant cells with ChIP at defined DSBs and repair kinetics assays","pmids":["23146902"],"confidence":"High","gaps":["Identity of phospho-NBN binding partners mediating retention not defined","Structural basis of phosphorylation-dependent recruitment unknown"]},{"year":2013,"claim":"Extended NBN function to CNS development, showing nibrin loss triggers ATM-Chk2 apoptosis and AKT/mTOR proliferation defects in oligodendrocyte precursors causing hypomyelination.","evidence":"Nestin-Cre conditional Nbn knockout mouse with pathway immunoblotting and BDNF/NGF rescue","pmids":["24272991"],"confidence":"Medium","gaps":["Direct molecular link between NBN and AKT/mTOR regulation not established","Whether OPC phenotype reflects DSB repair failure or a separate NBN function unclear"]},{"year":2014,"claim":"Mapped the NBN interactome and showed that a disease-derived FHA/BRCT1-containing p26 fragment aberrantly binds and inhibits PARP1, linking NBN truncation to persistent ROS and DSBs.","evidence":"Affinity-MS interactome from HEK293 with co-IP of p26-PARP1 and NAD+ activity assay; plus functional analysis of the p.R215W allele showing loss of NBN foci and PARP-inhibitor hypersensitivity","pmids":["25485873","24928521"],"confidence":"Medium","gaps":["Physiological relevance of p26-PARP1 inhibition versus loss of full-length NBN unresolved","Interactome partners not validated by reciprocal IP"]},{"year":2017,"claim":"Identified NBN (and ATM) as Hsp90α clients, establishing chaperone-dependent stability as a prerequisite for NBN-mediated MRN nuclear localization and DDR signaling.","evidence":"Reciprocal Co-IP of Hsp90α with NBN/ATM, 17-AAG inhibition with proteasome rescue, fractionation, and phospho-readouts (BRCA1, CHK2)","pmids":["28631426"],"confidence":"High","gaps":["Hsp90α binding region on NBN not mapped","Whether chaperone dependence is constitutive or damage-regulated not fully defined"]},{"year":2019,"claim":"Established that the NBN–MRE11 physical interaction is essential for tumor suppression and hematopoiesis, and that NBN sustains steady-state nuclear co-localization of MRN and ATM.","evidence":"Mouse Nbnmid8 binding-impaired allele with hematopoietic/tumor phenotyping and genomic analysis; human infertility variants producing p84-NBN with MRN/ATM cytoplasmic relocalization","pmids":["31285322","31729086"],"confidence":"High","gaps":["How weakened NBN-MRE11 binding mechanistically drives leukemogenesis beyond MRE11 amplification unresolved","Determinants distinguishing infertility-only phenotypes from classic NBS not defined"]},{"year":2023,"claim":"Showed that truncating NBN variants yield alternative-translation fragments that retain MRE11 binding yet fail to support ATM-dependent signaling, linking partial NBN function to radiosensitivity.","evidence":"Immunoblot detection of a 45 kDa fragment, co-IP with MRE11, γ-irradiation survival, and phospho-KAP1 readout","pmids":["36346689"],"confidence":"Medium","gaps":["Why MRE11-binding-competent fragments still fail to signal not mechanistically resolved","Single-lab, limited replication"]},{"year":null,"claim":"How NBN integrates its DSB-adapter role with oxidative-stress regulation and tissue-specific survival/proliferation signaling remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No molecular mechanism connecting NBN to ROS homeostasis","No structural model of phosphorylation-dependent MRN/ATM retention at breaks","Direct biochemical link between NBN and AKT/mTOR signaling unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9,2,7]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[9,2]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,8,4]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2,3,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[9,2,6]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,4,12]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[9,13]}],"complexes":["MRE11/RAD50/NBN (MRN) complex"],"partners":["MRE11","RAD50","ATM","HSP90AA1","PARP1","P53","PML"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60934","full_name":"Nibrin","aliases":["Cell cycle regulatory protein p95","Nijmegen breakage syndrome protein 1","hNbs1"],"length_aa":754,"mass_kda":85.0,"function":"Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis (PubMed:10888888, PubMed:15616588, PubMed:18411307, PubMed:18583988, PubMed:18678890, PubMed:19759395, PubMed:23115235, PubMed:28216226, PubMed:28867292, PubMed:9705271). The MRN complex is involved in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR), an error-free mechanism which primarily occurs during S and G2 phases (PubMed:19759395, PubMed:28867292, PubMed:9705271). The complex (1) mediates the end resection of damaged DNA, which generates proper single-stranded DNA, a key initial steps in HR, and is (2) required for the recruitment of other repair factors and efficient activation of ATM and ATR upon DNA damage (PubMed:19759395, PubMed:9705271). The MRN complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11, to initiate end resection, which is required for single-strand invasion and recombination (PubMed:19759395, PubMed:28867292, PubMed:9705271). Within the MRN complex, NBN acts as a protein-protein adapter, which specifically recognizes and binds phosphorylated proteins, promoting their recruitment to DNA damage sites (PubMed:12419185, PubMed:15616588, PubMed:18411307, PubMed:18582474, PubMed:18583988, PubMed:18678890, PubMed:19759395, PubMed:19804756, PubMed:23762398, PubMed:24534091, PubMed:27814491, PubMed:27889449, PubMed:33836577). Recruits MRE11 and RAD50 components of the MRN complex to DSBs in response to DNA damage (PubMed:12419185, PubMed:18411307, PubMed:18583988, PubMed:18678890, PubMed:24534091, PubMed:26438602). Promotes the recruitment of PI3/PI4-kinase family members ATM, ATR, and probably DNA-PKcs to the DNA damage sites, activating their functions (PubMed:15064416, PubMed:15616588, PubMed:15790808, PubMed:16622404, PubMed:22464731, PubMed:30952868, PubMed:35076389). Mediates the recruitment of phosphorylated RBBP8/CtIP to DSBs, leading to cooperation between the MRN complex and RBBP8/CtIP to initiate end resection (PubMed:19759395, PubMed:27814491, PubMed:27889449, PubMed:33836577). RBBP8/CtIP specifically promotes the endonuclease activity of the MRN complex to clear DNA ends containing protein adducts (PubMed:27814491, PubMed:27889449, PubMed:30787182, PubMed:33836577). The MRN complex is also required for the processing of R-loops (PubMed:31537797). NBN also functions in telomere length maintenance via its interaction with TERF2: interaction with TERF2 during G1 phase preventing recruitment of DCLRE1B/Apollo to telomeres (PubMed:10888888, PubMed:28216226). NBN also promotes DNA repair choice at dysfunctional telomeres: NBN phosphorylation by CDK2 promotes non-homologous end joining repair at telomeres, while unphosphorylated NBN promotes microhomology-mediated end-joining (MMEJ) repair (PubMed:28216226). Enhances AKT1 phosphorylation possibly by association with the mTORC2 complex (PubMed:23762398)","subcellular_location":"Nucleus; Chromosome; Nucleus, PML body; Chromosome, telomere","url":"https://www.uniprot.org/uniprotkb/O60934/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NBN","classification":"Not Classified","n_dependent_lines":27,"n_total_lines":1208,"dependency_fraction":0.022350993377483443},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NBN","total_profiled":1310},"omim":[{"mim_id":"617154","title":"MRN COMPLEX-INTERACTING PROTEIN; MRNIP","url":"https://www.omim.org/entry/617154"},{"mim_id":"616940","title":"EXONUCLEASE 3-PRIME-TO-5-PRIME DOMAIN-CONTAINING PROTEIN 2; EXD2","url":"https://www.omim.org/entry/616940"},{"mim_id":"615667","title":"ERCC EXCISION REPAIR 6-LIKE 2; ERCC6L2","url":"https://www.omim.org/entry/615667"},{"mim_id":"613273","title":"INST3- AND NABP-INTERACTING PROTEIN; INIP","url":"https://www.omim.org/entry/613273"},{"mim_id":"611347","title":"INTEGRATOR COMPLEX SUBUNIT 3; INTS3","url":"https://www.omim.org/entry/611347"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Mitotic chromosome","reliability":"Additional"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NBN"},"hgnc":{"alias_symbol":["ATV","AT-V2","AT-V1"],"prev_symbol":["NBS","NBS1"]},"alphafold":{"accession":"O60934","domains":[{"cath_id":"2.60.200.20","chopping":"3-112","consensus_level":"high","plddt":88.1539,"start":3,"end":112},{"cath_id":"3.40.50.10190","chopping":"114-215","consensus_level":"medium","plddt":90.2156,"start":114,"end":215},{"cath_id":"3.40.50.10980","chopping":"220-328","consensus_level":"medium","plddt":86.9739,"start":220,"end":328}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60934","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60934-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60934-F1-predicted_aligned_error_v6.png","plddt_mean":63.09},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NBN","jax_strain_url":"https://www.jax.org/strain/search?query=NBN"},"sequence":{"accession":"O60934","fasta_url":"https://rest.uniprot.org/uniprotkb/O60934.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60934/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60934"}},"corpus_meta":[{"pmid":"17110940","id":"PMC_17110940","title":"Plant NBS-LRR proteins in pathogen sensing and host defense.","date":"2006","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17110940","citation_count":462,"is_preprint":false},{"pmid":"26315354","id":"PMC_26315354","title":"Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer.","date":"2015","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/26315354","citation_count":330,"is_preprint":false},{"pmid":"15231261","id":"PMC_15231261","title":"Plant disease resistance protein signaling: NBS-LRR proteins and their partners.","date":"2004","source":"Current opinion in plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/15231261","citation_count":322,"is_preprint":false},{"pmid":"12198153","id":"PMC_12198153","title":"Interaction between domains of a plant NBS-LRR protein in disease resistance-related cell death.","date":"2002","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12198153","citation_count":312,"is_preprint":false},{"pmid":"18563445","id":"PMC_18563445","title":"Recent duplications dominate NBS-encoding gene expansion in two woody species.","date":"2008","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/18563445","citation_count":294,"is_preprint":false},{"pmid":"23549266","id":"PMC_23549266","title":"Plant nucleotide binding site-leucine-rich repeat (NBS-LRR) genes: active guardians in host defense responses.","date":"2013","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/23549266","citation_count":195,"is_preprint":false},{"pmid":"22373003","id":"PMC_22373003","title":"Nijmegen breakage syndrome (NBS).","date":"2012","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/22373003","citation_count":174,"is_preprint":false},{"pmid":"11896594","id":"PMC_11896594","title":"PML NBs associate with the hMre11 complex and p53 at sites of irradiation induced DNA damage.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11896594","citation_count":155,"is_preprint":false},{"pmid":"11956693","id":"PMC_11956693","title":"Diversity, distribution, and ancient taxonomic relationships within the TIR and non-TIR NBS-LRR resistance gene subfamilies.","date":"2002","source":"Journal of molecular evolution","url":"https://pubmed.ncbi.nlm.nih.gov/11956693","citation_count":134,"is_preprint":false},{"pmid":"24391949","id":"PMC_24391949","title":"miR482 regulation of NBS-LRR defense genes during fungal pathogen infection in cotton.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24391949","citation_count":133,"is_preprint":false},{"pmid":"18931695","id":"PMC_18931695","title":"Regulation of apoptosis by PML and the PML-NBs.","date":"2008","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/18931695","citation_count":127,"is_preprint":false},{"pmid":"14612522","id":"PMC_14612522","title":"Nbn heterozygosity renders mice susceptible to tumor formation and ionizing radiation-induced tumorigenesis.","date":"2003","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/14612522","citation_count":119,"is_preprint":false},{"pmid":"15122516","id":"PMC_15122516","title":"Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving ATV-containing regimens.","date":"2004","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/15122516","citation_count":118,"is_preprint":false},{"pmid":"25948536","id":"PMC_25948536","title":"Identification and distribution of the NBS-LRR gene family in the Cassava genome.","date":"2015","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/25948536","citation_count":106,"is_preprint":false},{"pmid":"25336565","id":"PMC_25336565","title":"The stripe rust resistance gene Yr10 encodes an evolutionary-conserved and unique CC-NBS-LRR sequence in wheat.","date":"2014","source":"Molecular plant","url":"https://pubmed.ncbi.nlm.nih.gov/25336565","citation_count":105,"is_preprint":false},{"pmid":"25650828","id":"PMC_25650828","title":"Pi64, Encoding a Novel CC-NBS-LRR Protein, Confers Resistance to Leaf and Neck Blast in Rice.","date":"2015","source":"Molecular plant-microbe interactions : MPMI","url":"https://pubmed.ncbi.nlm.nih.gov/25650828","citation_count":95,"is_preprint":false},{"pmid":"28096345","id":"PMC_28096345","title":"The NBS-LRR architectures of plant R-proteins and metazoan NLRs evolved in independent events.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28096345","citation_count":95,"is_preprint":false},{"pmid":"16677670","id":"PMC_16677670","title":"Structural and genomic properties of the hyperthermophilic archaeal virus ATV with an extracellular stage of the reproductive cycle.","date":"2006","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16677670","citation_count":91,"is_preprint":false},{"pmid":"19171781","id":"PMC_19171781","title":"Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS.","date":"2009","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/19171781","citation_count":81,"is_preprint":false},{"pmid":"20888667","id":"PMC_20888667","title":"Transcriptional analysis in high-anthocyanin tomatoes reveals synergistic effect of Aft and atv genes.","date":"2011","source":"Journal of plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20888667","citation_count":73,"is_preprint":false},{"pmid":"18073374","id":"PMC_18073374","title":"Cancer risk of heterozygotes with the NBN founder mutation.","date":"2007","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/18073374","citation_count":69,"is_preprint":false},{"pmid":"25935646","id":"PMC_25935646","title":"Extreme expansion of NBS-encoding genes in Rosaceae.","date":"2015","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25935646","citation_count":54,"is_preprint":false},{"pmid":"30957942","id":"PMC_30957942","title":"The Gossypium hirsutum TIR-NBS-LRR gene GhDSC1 mediates resistance against Verticillium wilt.","date":"2019","source":"Molecular plant pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30957942","citation_count":49,"is_preprint":false},{"pmid":"18508722","id":"PMC_18508722","title":"PML NBs (ND10) and Daxx: from nuclear structure to protein function.","date":"2008","source":"Frontiers in bioscience : a journal and virtual library","url":"https://pubmed.ncbi.nlm.nih.gov/18508722","citation_count":48,"is_preprint":false},{"pmid":"12715163","id":"PMC_12715163","title":"Barley disease resistance gene analogs of the NBS-LRR class: identification and mapping.","date":"2003","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/12715163","citation_count":48,"is_preprint":false},{"pmid":"16648644","id":"PMC_16648644","title":"The Drosophila Nbs protein functions in multiple pathways for the maintenance of genome stability.","date":"2006","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16648644","citation_count":46,"is_preprint":false},{"pmid":"30802599","id":"PMC_30802599","title":"Genome-wide characterization revealed role of NBS-LRR genes during powdery mildew infection in Vitis vinifera.","date":"2019","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/30802599","citation_count":46,"is_preprint":false},{"pmid":"12582850","id":"PMC_12582850","title":"Characterization of expressed NBS-LRR resistance gene candidates from common bean.","date":"2002","source":"TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/12582850","citation_count":41,"is_preprint":false},{"pmid":"26793216","id":"PMC_26793216","title":"The Eucalyptus grandis NBS-LRR Gene Family: Physical Clustering and Expression Hotspots.","date":"2016","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/26793216","citation_count":40,"is_preprint":false},{"pmid":"11459185","id":"PMC_11459185","title":"Origin, diversity and evolution of NBS-type disease-resistance gene homologues in coffee trees (Coffea L.).","date":"2001","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/11459185","citation_count":40,"is_preprint":false},{"pmid":"25475390","id":"PMC_25475390","title":"Dynamic evolution of NBS-LRR genes in bread wheat and its progenitors.","date":"2014","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/25475390","citation_count":40,"is_preprint":false},{"pmid":"30535849","id":"PMC_30535849","title":"Over-expression of GmKR3, a TIR-NBS-LRR type R gene, confers resistance to multiple viruses in soybean.","date":"2018","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30535849","citation_count":39,"is_preprint":false},{"pmid":"32875559","id":"PMC_32875559","title":"Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland.","date":"2020","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32875559","citation_count":36,"is_preprint":false},{"pmid":"32457809","id":"PMC_32457809","title":"Genome-Wide Identification and Evolutionary Analysis of NBS-LRR Genes From Dioscorea rotundata.","date":"2020","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32457809","citation_count":33,"is_preprint":false},{"pmid":"12708449","id":"PMC_12708449","title":"Chromosome instability and nibrin protein variants in NBS heterozygotes.","date":"2003","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/12708449","citation_count":32,"is_preprint":false},{"pmid":"31270546","id":"PMC_31270546","title":"A CC-NBS-LRR gene induces hybrid lethality in cotton.","date":"2019","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/31270546","citation_count":32,"is_preprint":false},{"pmid":"28631426","id":"PMC_28631426","title":"Hsp90α regulates ATM and NBN functions in sensing and repair of DNA double-strand breaks.","date":"2017","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/28631426","citation_count":29,"is_preprint":false},{"pmid":"30303765","id":"PMC_30303765","title":"Rpp1 Encodes a ULP1-NBS-LRR Protein That Controls Immunity to Phakopsora pachyrhizi in Soybean.","date":"2018","source":"Molecular plant-microbe interactions : MPMI","url":"https://pubmed.ncbi.nlm.nih.gov/30303765","citation_count":29,"is_preprint":false},{"pmid":"25415046","id":"PMC_25415046","title":"NBN gain is predictive for adverse outcome following image-guided radiotherapy for localized prostate cancer.","date":"2014","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25415046","citation_count":29,"is_preprint":false},{"pmid":"18937860","id":"PMC_18937860","title":"Transcriptional response of Mexican axolotls to Ambystoma tigrinum virus (ATV) infection.","date":"2008","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/18937860","citation_count":27,"is_preprint":false},{"pmid":"37227756","id":"PMC_37227756","title":"Interplay between PML NBs and HIRA for H3.3 dynamics following type I interferon stimulus.","date":"2023","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/37227756","citation_count":25,"is_preprint":false},{"pmid":"38153293","id":"PMC_38153293","title":"Two functional CC-NBS-LRR proteins from rye chromosome 6RS confer differential age-related powdery mildew resistance to wheat.","date":"2023","source":"Plant biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/38153293","citation_count":24,"is_preprint":false},{"pmid":"22544561","id":"PMC_22544561","title":"The potential link between PML NBs and ICP0 in regulating lytic and latent infection of HSV-1.","date":"2012","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/22544561","citation_count":23,"is_preprint":false},{"pmid":"31065502","id":"PMC_31065502","title":"Identification and expression profiling analysis of NBS-LRR genes involved in Fusarium oxysporum f.sp. conglutinans resistance in cabbage.","date":"2019","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/31065502","citation_count":22,"is_preprint":false},{"pmid":"35563438","id":"PMC_35563438","title":"Genome-Wide Identification and Characterization of the CC-NBS-LRR Gene Family in Cucumber (Cucumis sativus L.).","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35563438","citation_count":22,"is_preprint":false},{"pmid":"34567025","id":"PMC_34567025","title":"Cotton CC-NBS-LRR Gene GbCNL130 Confers Resistance to Verticillium Wilt Across Different Species.","date":"2021","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/34567025","citation_count":22,"is_preprint":false},{"pmid":"34654619","id":"PMC_34654619","title":"Natural history of children and adults with phenylketonuria in the NBS-PKU Connect registry.","date":"2021","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/34654619","citation_count":22,"is_preprint":false},{"pmid":"32061771","id":"PMC_32061771","title":"NOSH-aspirin (NBS-1120) inhibits pancreatic cancer cell growth in a xenograft mouse model: Modulation of FoxM1, p53, NF-κB, iNOS, caspase-3 and ROS.","date":"2020","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32061771","citation_count":22,"is_preprint":false},{"pmid":"30590007","id":"PMC_30590007","title":"Inherited NBN Mutations and Prostate Cancer Risk and Survival.","date":"2018","source":"Cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/30590007","citation_count":21,"is_preprint":false},{"pmid":"36388562","id":"PMC_36388562","title":"PM2b, a CC-NBS-LRR protein, interacts with TaWRKY76-D to regulate powdery mildew resistance in common wheat.","date":"2022","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/36388562","citation_count":21,"is_preprint":false},{"pmid":"23146902","id":"PMC_23146902","title":"NBN phosphorylation regulates the accumulation of MRN and ATM at sites of DNA double-strand breaks.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23146902","citation_count":21,"is_preprint":false},{"pmid":"32245073","id":"PMC_32245073","title":"NLGenomeSweeper: A Tool for Genome-Wide NBS-LRR Resistance Gene Identification.","date":"2020","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/32245073","citation_count":21,"is_preprint":false},{"pmid":"34777439","id":"PMC_34777439","title":"Identification and Characterization of NBS Resistance Genes in Akebia trifoliata.","date":"2021","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/34777439","citation_count":20,"is_preprint":false},{"pmid":"36346689","id":"PMC_36346689","title":"NBN Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and In Vitro DNA Damage Response Defects.","date":"2023","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/36346689","citation_count":19,"is_preprint":false},{"pmid":"24396275","id":"PMC_24396275","title":"NBN Gene Polymorphisms and Cancer Susceptibility: A Systemic Review.","date":"2013","source":"Current genomics","url":"https://pubmed.ncbi.nlm.nih.gov/24396275","citation_count":19,"is_preprint":false},{"pmid":"26998278","id":"PMC_26998278","title":"Association of the nibrin gene (NBN) variants with breast cancer.","date":"2016","source":"Biomedical reports","url":"https://pubmed.ncbi.nlm.nih.gov/26998278","citation_count":19,"is_preprint":false},{"pmid":"33461498","id":"PMC_33461498","title":"Genome-wide identification and characterization of NBS-encoding genes in Raphanus sativus L. and their roles related to Fusarium oxysporum resistance.","date":"2021","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/33461498","citation_count":19,"is_preprint":false},{"pmid":"36982687","id":"PMC_36982687","title":"Importance of Germline and Somatic Alterations in Human MRE11, RAD50, and NBN Genes Coding for MRN Complex.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36982687","citation_count":18,"is_preprint":false},{"pmid":"38408951","id":"PMC_38408951","title":"Functional characterization of NBS-LRR genes reveals an NBS-LRR gene that mediates resistance against Fusarium wilt.","date":"2024","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/38408951","citation_count":18,"is_preprint":false},{"pmid":"25485873","id":"PMC_25485873","title":"Identification of the interactors of human nibrin (NBN) and of its 26 kDa and 70 kDa fragments arising from the NBN 657del5 founder mutation.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25485873","citation_count":18,"is_preprint":false},{"pmid":"32966899","id":"PMC_32966899","title":"A Rice NBS-ARC Gene Conferring Quantitative Resistance to Bacterial Blight Is Regulated by a Pathogen Effector-Inducible miRNA.","date":"2020","source":"Molecular plant","url":"https://pubmed.ncbi.nlm.nih.gov/32966899","citation_count":18,"is_preprint":false},{"pmid":"34160845","id":"PMC_34160845","title":"Ne2, a typical CC-NBS-LRR-type gene, is responsible for hybrid necrosis in wheat.","date":"2021","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/34160845","citation_count":17,"is_preprint":false},{"pmid":"33924035","id":"PMC_33924035","title":"Genome-Wide Identification and Analysis of CC-NBS-LRR Family in Response to Downy Mildew and Black Rot in Chinese Cabbage.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33924035","citation_count":17,"is_preprint":false},{"pmid":"37933299","id":"PMC_37933299","title":"IR-820@NBs Combined with MG-132 Enhances the Anti-Hepatocellular Carcinoma Effect of Sonodynamic Therapy.","date":"2023","source":"International journal of nanomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/37933299","citation_count":15,"is_preprint":false},{"pmid":"35903220","id":"PMC_35903220","title":"RppM, Encoding a Typical CC-NBS-LRR Protein, Confers Resistance to Southern Corn Rust in Maize.","date":"2022","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/35903220","citation_count":15,"is_preprint":false},{"pmid":"27936167","id":"PMC_27936167","title":"The Slavic NBN Founder Mutation: A Role for Reproductive Fitness?","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27936167","citation_count":15,"is_preprint":false},{"pmid":"21982819","id":"PMC_21982819","title":"AAA ATPase p529 of Acidianus two-tailed virus ATV and host receptor recognition.","date":"2011","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/21982819","citation_count":15,"is_preprint":false},{"pmid":"34072463","id":"PMC_34072463","title":"Detecting Variants in the NBN Gene While Testing for Hereditary Breast Cancer: What to Do Next?","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34072463","citation_count":15,"is_preprint":false},{"pmid":"20729302","id":"PMC_20729302","title":"Nijmegen breakage syndrome protein (NBN) causes resistance to methylating anticancer drugs such as temozolomide.","date":"2010","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20729302","citation_count":15,"is_preprint":false},{"pmid":"24093751","id":"PMC_24093751","title":"Germline variants in MRE11/RAD50/NBN complex genes in childhood leukemia.","date":"2013","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24093751","citation_count":15,"is_preprint":false},{"pmid":"29232653","id":"PMC_29232653","title":"Salicylic acid and broad spectrum of NBS-LRR family genes are involved in SMV-soybean interactions.","date":"2017","source":"Plant physiology and biochemistry : PPB","url":"https://pubmed.ncbi.nlm.nih.gov/29232653","citation_count":15,"is_preprint":false},{"pmid":"24928521","id":"PMC_24928521","title":"Functional deficiency of NBN, the Nijmegen breakage syndrome protein, in a p.R215W mutant breast cancer cell line.","date":"2014","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24928521","citation_count":15,"is_preprint":false},{"pmid":"36737455","id":"PMC_36737455","title":"On the interplay between lipids and asymmetric dynamics of an NBS degenerate ABC transporter.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/36737455","citation_count":14,"is_preprint":false},{"pmid":"33339169","id":"PMC_33339169","title":"Mutation Spectra of the MRN (MRE11, RAD50, NBS1/NBN) Break Sensor in Cancer Cells.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33339169","citation_count":14,"is_preprint":false},{"pmid":"29467425","id":"PMC_29467425","title":"Genome-scale examination of NBS-encoding genes in blueberry.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29467425","citation_count":14,"is_preprint":false},{"pmid":"36522328","id":"PMC_36522328","title":"Filamentous nuclear actin regulation of PML NBs during the DNA damage response is deregulated by prelamin A.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36522328","citation_count":14,"is_preprint":false},{"pmid":"30190132","id":"PMC_30190132","title":"OsCML16 interacts with a novel CC-NBS-LRR protein OsPi304 in the Ca2+/Mg2+ dependent and independent manner in rice.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30190132","citation_count":14,"is_preprint":false},{"pmid":"33272575","id":"PMC_33272575","title":"Structure and function analysis of a CC-NBS-LRR protein AT1G12290.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33272575","citation_count":13,"is_preprint":false},{"pmid":"36424366","id":"PMC_36424366","title":"An NBS-LRR protein in the Rpp1 locus negates the dominance of Rpp1-mediated resistance against Phakopsora pachyrhizi in soybean.","date":"2023","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/36424366","citation_count":13,"is_preprint":false},{"pmid":"37489488","id":"PMC_37489488","title":"Is Our Newborn Screening Working Well? A Literature Review of Quality Requirements for Newborn Blood Spot Screening (NBS) Infrastructure and Procedures.","date":"2023","source":"International journal of neonatal screening","url":"https://pubmed.ncbi.nlm.nih.gov/37489488","citation_count":13,"is_preprint":false},{"pmid":"19635536","id":"PMC_19635536","title":"Clinical variability and expression of the NBN c.657del5 allele in Nijmegen Breakage Syndrome.","date":"2009","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/19635536","citation_count":13,"is_preprint":false},{"pmid":"24272991","id":"PMC_24272991","title":"DNA damage and oxidative injury are associated with hypomyelination in the corpus callosum of newborn Nbn(CNS-del) mice.","date":"2013","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/24272991","citation_count":13,"is_preprint":false},{"pmid":"34638580","id":"PMC_34638580","title":"Identification and Cloning of a CC-NBS-NBS-LRR Gene as a Candidate of Pm40 by Integrated Analysis of Both the Available Transcriptional Data and Published Linkage Mapping.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34638580","citation_count":13,"is_preprint":false},{"pmid":"31285322","id":"PMC_31285322","title":"Nbn-Mre11 interaction is required for tumor suppression and genomic integrity.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31285322","citation_count":12,"is_preprint":false},{"pmid":"25231182","id":"PMC_25231182","title":"Full-genome identification and characterization of NBS-encoding disease resistance genes in wheat.","date":"2014","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/25231182","citation_count":12,"is_preprint":false},{"pmid":"35001170","id":"PMC_35001170","title":"SUMOylation regulates the number and size of promyelocytic leukemia-nuclear bodies (PML-NBs) and arsenic perturbs SUMO dynamics on PML by insolubilizing PML in THP-1 cells.","date":"2022","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35001170","citation_count":12,"is_preprint":false},{"pmid":"30477134","id":"PMC_30477134","title":"Segmental and Tandem Duplications Driving the Recent NBS-LRR Gene Expansion in the Asparagus Genome.","date":"2018","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/30477134","citation_count":12,"is_preprint":false},{"pmid":"30792163","id":"PMC_30792163","title":"Therapeutic Intranasal Vaccine HB-ATV-8 Prevents Atherogenesis and Non-alcoholic Fatty Liver Disease in a Pig Model of Atherosclerosis.","date":"2019","source":"Archives of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/30792163","citation_count":12,"is_preprint":false},{"pmid":"31410679","id":"PMC_31410679","title":"Allelic modification of breast cancer risk in women with an NBN mutation.","date":"2019","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/31410679","citation_count":12,"is_preprint":false},{"pmid":"37268110","id":"PMC_37268110","title":"Indispensable biomolecules for plant defense against pathogens: NBS-LRR and \"nitrogen pool\" alkaloids.","date":"2023","source":"Plant science : an international journal of experimental plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/37268110","citation_count":11,"is_preprint":false},{"pmid":"39516573","id":"PMC_39516573","title":"Promises and challenges of genomic newborn screening (NBS) - lessons from public health NBS programs.","date":"2024","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/39516573","citation_count":11,"is_preprint":false},{"pmid":"35351660","id":"PMC_35351660","title":"NBS-LRR-WRKY genes and protease inhibitors (PIs) seem essential for cowpea resistance to root-knot nematode.","date":"2022","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/35351660","citation_count":11,"is_preprint":false},{"pmid":"35178059","id":"PMC_35178059","title":"The Cassava NBS-LRR Genes Confer Resistance to Cassava Bacterial Blight.","date":"2022","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/35178059","citation_count":11,"is_preprint":false},{"pmid":"34858486","id":"PMC_34858486","title":"Genome-wide Identification and Evolutionary Analysis of NBS-LRR Genes From Secale cereale.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34858486","citation_count":11,"is_preprint":false},{"pmid":"28844332","id":"PMC_28844332","title":"The Ambystoma tigrinum virus (ATV) RNase III gene can modulate host PKR activation and interferon production.","date":"2017","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/28844332","citation_count":11,"is_preprint":false},{"pmid":"27348446","id":"PMC_27348446","title":"Tracking ancestral lineages and recent expansions of NBS-LRR genes in angiosperms.","date":"2016","source":"Plant signaling & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/27348446","citation_count":11,"is_preprint":false},{"pmid":"19412544","id":"PMC_19412544","title":"A systematic proteomic study of irradiated DNA repair deficient Nbn-mice.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19412544","citation_count":11,"is_preprint":false},{"pmid":"31729086","id":"PMC_31729086","title":"DNA repair functional analyses of NBN hypomorphic variants associated with NBN-related infertility.","date":"2019","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/31729086","citation_count":10,"is_preprint":false},{"pmid":"20453309","id":"PMC_20453309","title":"High prevalence of the NBN gene mutation c.657-661del5 in Southeast Germany.","date":"2010","source":"Journal of applied genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20453309","citation_count":10,"is_preprint":false},{"pmid":"36139526","id":"PMC_36139526","title":"NBN, RAD51 and XRCC3 Polymorphisms as Potential Predictive Biomarkers of Adjuvant Radiotherapy Toxicity in Early HER2-Positive Breast Cancer.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36139526","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50710,"output_tokens":4250,"usd":0.10794,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12292,"output_tokens":3949,"usd":0.080092,"stage2_stop_reason":"end_turn"},"total_usd":0.188032,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"Drosophila Nbs mediates nuclear transport of the Mre11/Rad50 complex: Rad50 accumulates in nuclei of wild-type cells but not in nbs mutant cells, indicating Nbs is required for nuclear localization of the MRN complex. Epistasis analysis showed nbs functions in both ATM- and ATR-controlled telomere protection pathways, while all three MRN components function in a single pathway for DNA-damage-induced chromosome break repair.\",\n      \"method\": \"Genetic epistasis analysis in Drosophila nbs mutants; immunofluorescence/fractionation showing Rad50 nuclear localization; double-mutant analysis with tefu (ATM) and mei-41 (ATR)\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence, epistasis in multiple double-mutant backgrounds, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"16648644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In the nervous system, NBS1 (Nbs1) is required for normal ATM-dependent apoptosis after DNA damage: Nbs1ΔB/ΔB neural tissue shows defective ATM phosphorylation yet normal apoptosis, whereas Mre11ATLD1/ATLD1 tissue shows defective ATM activation and pronounced resistance to apoptosis. Genetic rescue experiments showed Mre11 and ATM backgrounds (but not Nbs1ΔB) rescue Lig4-induced microcephaly, placing Nbs1 and Mre11 in distinct sub-pathways for neural ATM signaling.\",\n      \"method\": \"Mouse conditional genetics; epistasis (Lig4 loss on Nbs1ΔB, Mre11ATLD1, Atm−/− backgrounds); immunoblotting for ATM substrates (Chk2, p53 phosphorylation); TUNEL apoptosis assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic epistasis experiments, defined phosphorylation readouts, replicated across multiple mutant backgrounds in a single rigorous study\",\n      \"pmids\": [\"19171781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ATM phosphorylation of NBN regulates the kinetics of NBN and ATM accumulation at DNA double-strand break sites: phospho-blocking (Ser→Ala) mutations delayed recruitment of both NBN and ATM to DSBs, while phosphomimetic (Ser→Glu) substitutions increased and prolonged their accumulation. Full-length NBN was required for timely DSB repair.\",\n      \"method\": \"Direct protein transduction of site-specific endonuclease I-PpoI into isogenic cell lines expressing NBN phosphorylation mutants; chromatin immunoprecipitation at defined DSB sites; DSB repair kinetics assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-specific DSB system with isogenic phosphorylation mutant cell lines, ChIP quantification, and DSB repair assays; multiple orthogonal methods in one study\",\n      \"pmids\": [\"23146902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"After ionizing radiation, PML nuclear bodies associate with the hMre11/Rad50/NBS1 complex at sites of DNA double-strand breaks (marked by γ-H2AX), and ionizing radiation induces stable physical association of p53 with hMre11 and PML within these foci.\",\n      \"method\": \"Immunofluorescence co-localization with anti-γ-H2AX; co-immunoprecipitation of p53 with hMre11 and PML after IR in normal human fibroblasts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and immunofluorescence co-localization, single lab, two orthogonal methods\",\n      \"pmids\": [\"11896594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NBN (nibrin) and ATM are clients of the molecular chaperone Hsp90α: inhibition of Hsp90α ATPase activity with 17-AAG causes polyubiquitination and proteasomal degradation of ATM and NBN (but not 53BP1, RAD50, or MRE11). Hsp90α–ATM and Hsp90α–NBN complexes exist in unstressed and irradiated cells. Upon IR-induced DSBs, ATM phosphorylates NBN, which then dissociates from Hsp90α and translocates to DSB sites. Hsp90α inhibition impairs nuclear localization of MRE11 and RAD50, attenuates DDR signaling (BRCA1, CHK2 phosphorylation), and slows DSB repair.\",\n      \"method\": \"Co-immunoprecipitation of Hsp90α with ATM and NBN; 17-AAG inhibitor treatment with proteasome inhibitor rescue; immunofluorescence for MRE11/RAD50 nuclear localization; immunoblotting for phospho-NBN, phospho-BRCA1, phospho-CHK2; subcellular fractionation\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, pharmacological inhibition with rescue, multiple phosphorylation readouts, localization experiments with functional consequence, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"28631426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Full-length NBN protein interacts with a broad set of partners involved in DNA damage response, ROS scavenging, and protein folding. The 26 kDa fragment (p26, containing FHA/BRCT1 domains) arising from the NBS founder mutation 657del5 interacts with PARP1 after irradiation, and this interaction inhibits PARP1 activity (measured by NAD+ levels) and is associated with persistence of ROS and DSBs at 24 h post-IR.\",\n      \"method\": \"Affinity chromatography from transiently transfected HEK293 cells expressing full-length NBN, p26, or p70; SDS-PAGE separation and shotgun MS/MS protein identification; co-immunoprecipitation of p26 with PARP1; NAD+ assay for PARP1 activity\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — proteomics interactome plus co-IP and enzymatic activity assay for PARP1 inhibition by p26; single lab, two orthogonal methods for the PARP1 finding\",\n      \"pmids\": [\"25485873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NBN (nibrin) is required for cellular resistance to O6-methylguanine-inducing agents (e.g., temozolomide, MNNG): NBN-mutant NBS cells are hypersensitive to these agents through increased apoptosis and necrosis. MGMT over-expression abrogated the hypersensitivity, indicating the response is specifically triggered by O6-methylguanine lesions requiring DSB processing by the MRN complex. siRNA knockdown of NBN in melanoma cells recapitulated the temozolomide sensitization.\",\n      \"method\": \"Clonogenic survival and cell death assays in NBN-mutant patient fibroblasts and lymphoblastoid cells; MGMT expression rescue experiment; siRNA knockdown of NBN in melanoma cells followed by temozolomide treatment; apoptosis/necrosis quantification\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (patient cells + siRNA knockdown), MGMT rescue epistasis defining the responsible lesion type, multiple cell line systems, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"20729302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Physical interaction between Nbn and the Mre11-Rad50 core is required for tumor suppression and normal hematopoiesis: a mouse Nbn allele (Nbnmid8) with severely impaired Mre11 binding caused profound hematopoietic defects, B cell development blockage, and rapid T cell leukemia. Leukemias showed focal amplification of 9qA2 causing MRE11 overexpression, interpreted as compensation for the weakened Mre11-Nbn interaction.\",\n      \"method\": \"Mouse genetics (conditional hematopoietic expression of Nbnmid8); flow cytometry of thymus and bone marrow cellularity; genomic analysis of tumors; copy number and gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined binding-impaired mutant allele in vivo with clear hematopoietic and tumor phenotype readout, genomic analysis of compensatory amplification; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31285322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NBN variants causing isolated infertility produce an alternative p84-NBN protein (from in-frame exon 4-5 skipping) that retains the FHA domain but shows dramatically reduced protein levels and causes relocalization of the MRN complex from the nucleus to the cytoplasm. ATM also shifts from nucleus to cytoplasm in these cells, suggesting steady-state ATM–MRN nuclear co-localization depends on NBN. ATM pathway activation was partially preserved, and cell cycle checkpoint defects were milder than in typical NBS.\",\n      \"method\": \"Transcript analysis (RT-PCR, sequencing); immunoblotting for NBN protein variants; immunofluorescence for subcellular localization of MRN complex and ATM; ATM pathway activation assay (camptothecin treatment); cell cycle checkpoint analysis\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization experiments with functional consequence, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31729086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The MRN complex (MRE11/RAD50/NBN) functions as a DNA double-strand break sensor and initiates DNA repair by activating ATM kinase, which coordinates repair with p53-dependent cell cycle checkpoint arrest. NBN contributes the FHA and BRCT domains for interaction with phosphorylated substrates and acts as the adapter subunit linking the MRE11 nuclease/RAD50 ATPase core to downstream checkpoint signaling.\",\n      \"method\": \"Review synthesizing functional genetic and biochemical studies (co-immunoprecipitation, domain deletion analyses, patient cell studies cited across the field)\",\n      \"journal\": \"Current genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — review paper summarizing published functional data without presenting new primary experiments\",\n      \"pmids\": [\"24396275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Two novel NBN truncating variants (p.L19* and p.N71fs) produce a 45 kDa alternative-translation fragment that maintains binding to MRE11. Cells expressing these fragments show higher sensitivity to γ-irradiation and lower levels of radiation-induced KAP1 phosphorylation, indicating impaired ATM-dependent DDR signaling.\",\n      \"method\": \"Immunoblotting for alternative translation product; co-immunoprecipitation of 45 kDa fragment with MRE11; γ-irradiation survival assay; immunoblotting for phospho-KAP1\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP identifying MRE11 binding, functional readouts (radiation sensitivity + KAP1 phosphorylation), single lab, limited replication\",\n      \"pmids\": [\"36346689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The NBN p.R215W missense mutation in the hemizygous state impairs NBN protein levels and abolishes formation of NBN foci at DNA damage sites after irradiation. Cells are highly radiosensitive, show impaired γH2AX, MDC1, and 53BP1 focus formation, and are hypersensitive to PARP1 inhibition, consistent with a combined NBN/BRCA1 deficiency. ATM signaling was largely unaffected despite NBN focus deficiency.\",\n      \"method\": \"Immunocytochemistry for NBN, γH2AX, MDC1, 53BP1 foci after IR; immunoblotting for NBN protein; clonogenic radiosensitivity assay; flow cytometry for cell cycle; impedance measurement for PARP1 inhibitor sensitivity\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in a naturally occurring cancer cell line with defined mutation, single lab\",\n      \"pmids\": [\"24928521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Nibrin-deficient mouse cells show increased production of reactive oxygen species following induction of DSBs, implicating NBN in oxidative stress regulation in addition to DSB repair. Proteomic analysis revealed significant alterations in proteins involved in oxidative stress and cellular redox homeostasis in nibrin null mutant mice.\",\n      \"method\": \"Conditional null mutant mouse model; 2D-gel proteomics (~8,000 proteins resolved); ROS measurement in Nbn null mutant fibroblasts after DSB induction\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse knockout with proteomics and direct ROS measurement, single lab, two orthogonal methods\",\n      \"pmids\": [\"19412544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nbn gene inactivation in the CNS leads to defective proliferation and enhanced apoptosis of oligodendrocyte precursor cells (OPCs) causing hypomyelination of corpus callosum. ATM-Chk2 signaling drives apoptosis while AKT/mTOR signaling controls proliferation of Nbn-deficient OPCs; BDNF/NGF stimulation attenuates oxidative stress and restores OPC proliferation via AKT/mTOR/P70S6K.\",\n      \"method\": \"Nestin-Cre conditional Nbn knockout mouse; immunohistochemistry/immunofluorescence for myelin and OPC markers; immunoblotting for ATM-Chk2 and AKT/mTOR pathway components; BDNF/NGF rescue experiments\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional CNS knockout with defined pathway analysis and rescue experiments; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24272991\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NBN (nibrin) functions as the adapter subunit of the MRE11/RAD50/NBN (MRN) complex, where it mediates nuclear import of MRE11-RAD50, recruits the complex to DNA double-strand break (DSB) sites through its FHA/BRCT domains, and facilitates ATM kinase activation; ATM in turn phosphorylates NBN to regulate the kinetics of MRN and ATM accumulation at DSBs, promote S-phase checkpoint signaling, and enable timely DSB repair, with NBN also functioning as an Hsp90α client protein whose chaperone-dependent stability is required for proper DDR signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NBN (nibrin) is the adapter subunit of the MRE11/RAD50/NBN (MRN) complex, the sensor that detects DNA double-strand breaks (DSBs) and couples their repair to ATM-dependent checkpoint signaling [#9]. NBN is required for nuclear import of the MRE11-RAD50 core: loss of nibrin function leaves Rad50 cytoplasmic, and NBN-mutant alleles that reduce protein levels or disrupt the steady-state association redistribute both MRN and ATM from nucleus to cytoplasm [#0, #8]. The physical NBN–MRE11 interaction is itself essential, as an allele with impaired Mre11 binding causes hematopoietic failure and T cell leukemia driven by compensatory MRE11 amplification [#7]. At breaks, ATM phosphorylates NBN to set the kinetics of MRN and ATM accumulation at DSB sites and enable timely repair: phospho-blocking mutations delay recruitment while phosphomimetic substitutions prolong it [#2]. NBN-mediated DSB processing is also required to resolve O6-methylguanine-derived lesions, since MGMT overexpression abolishes the temozolomide hypersensitivity of NBN-deficient cells [#6]. Beyond canonical repair, nibrin restrains reactive-oxygen-species production after DSB induction [#12] and, in the developing CNS, governs oligodendrocyte precursor survival and proliferation through ATM-Chk2 and AKT/mTOR signaling, with its loss producing hypomyelination [#13]. NBN stability depends on the chaperone Hsp90\\u03b1: pharmacological Hsp90\\u03b1 inhibition triggers polyubiquitination and proteasomal degradation of NBN and ATM, impairs MRE11/RAD50 nuclear localization, and attenuates downstream BRCA1 and CHK2 phosphorylation [#4]. Patient-derived truncating and missense variants that abolish NBN focus formation or reduce protein levels confer radiosensitivity, impaired downstream focus formation, and PARP-inhibitor hypersensitivity [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that the MRN complex physically organizes into DSB-associated nuclear structures together with PML and p53, linking MRN to checkpoint factors at damage sites.\",\n      \"evidence\": \"Immunofluorescence co-localization with \\u03b3-H2AX and co-IP of p53 with hMre11/PML after IR in human fibroblasts\",\n      \"pmids\": [\"11896594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define NBN's specific contribution to PML/p53 recruitment\", \"Co-localization does not establish direct NBN binding to p53 or PML\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved that nibrin is required for nuclear import of the MRE11-RAD50 core, defining NBN's role as the adapter delivering the complex into the nucleus.\",\n      \"evidence\": \"Genetic epistasis and Rad50 localization in Drosophila nbs mutants with ATM/ATR double-mutant analysis\",\n      \"pmids\": [\"16648644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of NBN-mediated nuclear import (NLS usage, import machinery) not defined\", \"Drosophila ortholog may not fully recapitulate human domain functions\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Distinguished NBN from MRE11 in tissue-specific ATM signaling and revealed an unanticipated role for nibrin in restraining oxidative stress alongside DSB repair.\",\n      \"evidence\": \"Mouse conditional/null genetics with ATM-substrate immunoblotting and TUNEL; 2D-gel proteomics and ROS measurement in Nbn-null fibroblasts\",\n      \"pmids\": [\"19171781\", \"19412544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of NBN's ROS regulation not identified\", \"Whether oxidative phenotype is a direct NBN function or downstream of unrepaired DSBs unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed that MRN-dependent DSB processing is the basis of cellular resistance to O6-methylguanine lesions, defining a specific lesion type whose repair requires NBN.\",\n      \"evidence\": \"Clonogenic and cell-death assays in NBN-mutant patient cells and melanoma siRNA knockdown with MGMT rescue epistasis\",\n      \"pmids\": [\"20729302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Step at which NBN acts on O6-methylguanine-derived DSBs not defined\", \"Does not separate MRN nuclease activity from NBN adapter function\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that ATM phosphorylation of NBN feeds back to control the kinetics of MRN and ATM accumulation at breaks, establishing NBN phosphorylation as a timing regulator of the DDR.\",\n      \"evidence\": \"Site-specific I-PpoI endonuclease in isogenic NBN phospho-mutant cells with ChIP at defined DSBs and repair kinetics assays\",\n      \"pmids\": [\"23146902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of phospho-NBN binding partners mediating retention not defined\", \"Structural basis of phosphorylation-dependent recruitment unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended NBN function to CNS development, showing nibrin loss triggers ATM-Chk2 apoptosis and AKT/mTOR proliferation defects in oligodendrocyte precursors causing hypomyelination.\",\n      \"evidence\": \"Nestin-Cre conditional Nbn knockout mouse with pathway immunoblotting and BDNF/NGF rescue\",\n      \"pmids\": [\"24272991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between NBN and AKT/mTOR regulation not established\", \"Whether OPC phenotype reflects DSB repair failure or a separate NBN function unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped the NBN interactome and showed that a disease-derived FHA/BRCT1-containing p26 fragment aberrantly binds and inhibits PARP1, linking NBN truncation to persistent ROS and DSBs.\",\n      \"evidence\": \"Affinity-MS interactome from HEK293 with co-IP of p26-PARP1 and NAD+ activity assay; plus functional analysis of the p.R215W allele showing loss of NBN foci and PARP-inhibitor hypersensitivity\",\n      \"pmids\": [\"25485873\", \"24928521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of p26-PARP1 inhibition versus loss of full-length NBN unresolved\", \"Interactome partners not validated by reciprocal IP\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified NBN (and ATM) as Hsp90\\u03b1 clients, establishing chaperone-dependent stability as a prerequisite for NBN-mediated MRN nuclear localization and DDR signaling.\",\n      \"evidence\": \"Reciprocal Co-IP of Hsp90\\u03b1 with NBN/ATM, 17-AAG inhibition with proteasome rescue, fractionation, and phospho-readouts (BRCA1, CHK2)\",\n      \"pmids\": [\"28631426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hsp90\\u03b1 binding region on NBN not mapped\", \"Whether chaperone dependence is constitutive or damage-regulated not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that the NBN\\u2013MRE11 physical interaction is essential for tumor suppression and hematopoiesis, and that NBN sustains steady-state nuclear co-localization of MRN and ATM.\",\n      \"evidence\": \"Mouse Nbnmid8 binding-impaired allele with hematopoietic/tumor phenotyping and genomic analysis; human infertility variants producing p84-NBN with MRN/ATM cytoplasmic relocalization\",\n      \"pmids\": [\"31285322\", \"31729086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How weakened NBN-MRE11 binding mechanistically drives leukemogenesis beyond MRE11 amplification unresolved\", \"Determinants distinguishing infertility-only phenotypes from classic NBS not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed that truncating NBN variants yield alternative-translation fragments that retain MRE11 binding yet fail to support ATM-dependent signaling, linking partial NBN function to radiosensitivity.\",\n      \"evidence\": \"Immunoblot detection of a 45 kDa fragment, co-IP with MRE11, \\u03b3-irradiation survival, and phospho-KAP1 readout\",\n      \"pmids\": [\"36346689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why MRE11-binding-competent fragments still fail to signal not mechanistically resolved\", \"Single-lab, limited replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NBN integrates its DSB-adapter role with oxidative-stress regulation and tissue-specific survival/proliferation signaling remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism connecting NBN to ROS homeostasis\", \"No structural model of phosphorylation-dependent MRN/ATM retention at breaks\", \"Direct biochemical link between NBN and AKT/mTOR signaling unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 2, 7]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [9, 2]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 8, 4]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2, 3, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [9, 2, 6]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 4, 12]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [9, 13]}\n    ],\n    \"complexes\": [\"MRE11/RAD50/NBN (MRN) complex\"],\n    \"partners\": [\"MRE11\", \"RAD50\", \"ATM\", \"HSP90AA1\", \"PARP1\", \"p53\", \"PML\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}