{"gene":"ASPM","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2001,"finding":"Drosophila Asp (ASPM ortholog) is a 220-kDa microtubule-associated protein that localizes to spindle poles independently of functional centrosomes; in asp mutants, microtubule nucleation occurs normally but spindle pole focusing and central spindle organization are severely defective, leading to cytokinesis failure. Asp is required for aggregation of microtubules into focused spindle poles and for formation of the central spindle.","method":"Genetic mutant analysis (asp mutants), immunofluorescence, double mutant epistasis with asterless, colchicine treatment","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetics, imaging, epistasis) in single rigorous study; foundational Drosophila ortholog paper","pmids":["11352927"],"is_preprint":false},{"year":2001,"finding":"Drosophila Asp is a substrate of Polo kinase; Polo phosphorylates Asp in vitro, generating an MPM2 epitope. Polo and Asp co-immunoprecipitate and exist in a 25–38S complex. Phosphorylated Asp is required (together with gamma-tubulin) to restore microtubule aster nucleation in salt-stripped centrosomes, and extracts from polo mutant embryos fail this rescue unless supplemented with phosphorylated Asp or active Polo kinase.","method":"In vitro kinase assay, co-immunoprecipitation, sucrose gradient sedimentation, centrosome reconstitution assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro phosphorylation assay, reciprocal Co-IP, functional reconstitution; multiple orthogonal methods","pmids":["11283617"],"is_preprint":false},{"year":2005,"finding":"Human ASPM localizes to the centrosome during interphase and to spindle poles from prophase through telophase; siRNA-mediated downregulation of ASPM decreases endogenous BRCA1 protein levels, suggesting ASPM regulates BRCA1 at the centrosome/spindle pole.","method":"siRNA knockdown, immunofluorescence, Western blot","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct localization by immunofluorescence tied to BRCA1 functional consequence; single lab, two methods","pmids":["16123590"],"is_preprint":false},{"year":2005,"finding":"RNAi depletion of Drosophila Asp in S2 cells produces severe loss of spindle pole focus; Asp localizes to focused poles and is subtly mislocalized after dynein-dynactin depletion, indicating complex interdependence between dynein-dynactin, Asp, and KLP10A in spindle pole focusing and centrosome attachment.","method":"RNAi depletion, immunofluorescence, quantitative spindle analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi with defined cellular phenotype, epistasis-style analysis; single lab","pmids":["15888542"],"is_preprint":false},{"year":2007,"finding":"Human ASPM co-localizes with citron kinase (CITK) at the midbody ring during cytokinesis and co-immunoprecipitates with CITK from HeLa cell lysates and embryonic neuroepithelium. The N-terminal fragment of ASPM localizes to centrosomes/spindle poles, while the C-terminal fragment localizes to midbodies; all microcephaly-causing ASPM mutations truncate the C-terminus.","method":"Co-immunoprecipitation, GFP-fragment localization, immunofluorescence","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal Co-IP plus domain-mapping localization; moderate evidence from single lab","pmids":["17534152"],"is_preprint":false},{"year":2010,"finding":"Human ASPM is a microtubule minus-end-associated protein recruited in a microtubule-dependent manner to the pericentriolar matrix at spindle poles. siRNA depletion perturbs spindle orientation and causes cytokinesis failure in U2OS cells. A pathogenic splice-site mutation causing loss of a tripeptide from the C-terminus dramatically reduces ASPM spindle pole localization. Dominant-negative C-terminal ASPM fragments cause spindle assembly defects and cytokinesis failure.","method":"siRNA knockdown, immunofluorescence, live-cell imaging, patient fibroblast analysis, dominant-negative expression","journal":"BMC cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD phenotype, patient mutation analysis, dominant-negative, localization studies) converging on spindle pole function","pmids":["21044324"],"is_preprint":false},{"year":2011,"finding":"ASPM regulates Wnt signaling during brain development: Aspm knockdown in the developing mouse brain reduces Wnt-mediated transcription, and expression of stabilized β-catenin rescues both the signaling deficit and the in vivo cortical defects caused by Aspm knockdown.","method":"In utero electroporation knockdown, luciferase reporter assay, β-catenin rescue experiment","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — in vivo knockdown with specific rescue by activated β-catenin; multiple complementary approaches","pmids":["21937711"],"is_preprint":false},{"year":2012,"finding":"ASPM localizes to the entire spindle during mouse oocyte meiosis and co-localizes with acetylated tubulin. Morpholino-mediated knockdown causes elongated meiotic spindles and arrest at metaphase I. ASPM co-immunoprecipitates with calmodulin in metaphase I oocytes, and the two proteins co-localize at the spindle.","method":"Morpholino knockdown, immunofluorescence, co-immunoprecipitation, mass spectrometry","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — morpholino KD with defined spindle phenotype plus Co-IP/MS identification of calmodulin interaction; single lab","pmids":["23152892"],"is_preprint":false},{"year":2014,"finding":"In C. elegans, the calponin homology domain protein ASPM-1, together with the katanin MEI-1, is required for oocyte meiotic spindle pole assembly. MEI-1 recruits ASPM-1 to the spindle and also severs microtubules; both activities contribute to spindle bipolarity.","method":"Temperature-sensitive alleles, live-cell imaging, genetic epistasis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — live imaging with temperature-sensitive alleles and epistasis; ortholog study in C. elegans","pmids":["24554763"],"is_preprint":false},{"year":2015,"finding":"Drosophila Asp localizes to minus ends of spindle microtubule bundles and focuses them at poles independent of Ncd. An identified domain in Asp has microtubule cross-linking activity in vitro. Asp also localizes to minus ends of intraspindle augmin-dependent microtubules and focuses them toward poles during spindle flux.","method":"In vitro microtubule cross-linking assay, RNAi depletion, live-cell imaging, domain analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro MT cross-linking reconstitution plus live imaging of minus-end dynamics; multiple orthogonal methods","pmids":["26644514"],"is_preprint":false},{"year":2015,"finding":"ASPM interacts with the Cdk2/Cyclin E complex and modulates Cyclin E ubiquitination and phosphorylation, thereby regulating nuclear translocation of Cyclin E and the timing of restriction point passage in neural progenitors. ASPM-mutant mice show premature neural progenitor pool exhaustion due to shortened G1 before the restriction point.","method":"ASPM knock-in mouse model, co-immunoprecipitation, ubiquitination assay, cell cycle analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — mouse model plus Co-IP and ubiquitination assay; multiple orthogonal methods establishing the Cdk2/Cyclin E interaction","pmids":["26581405"],"is_preprint":false},{"year":2017,"finding":"ASPM forms a complex with the microtubule-severing ATPase katanin (p60/p80 heterodimer). X-ray crystallography revealed that the N- and C-terminal domains of katanin p60 and p80, respectively, bind conserved motifs in ASPM. Reconstitution experiments showed ASPM autonomously tracks growing microtubule minus ends and inhibits their growth; katanin potentiates this minus-end blocking and, together with ASPM, promotes microtubule severing. ASPM and katanin localize to spindle poles in a mutually dependent manner and regulate spindle flux.","method":"X-ray crystallography, in vitro microtubule reconstitution, TIRF microscopy, co-immunoprecipitation, siRNA knockdown","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure of ASPM-katanin interface, in vitro reconstitution of minus-end tracking and severing, multiple orthogonal methods in single study","pmids":["28436967"],"is_preprint":false},{"year":2017,"finding":"Human ASPM functions redundantly with CDK5RAP2 (CEP215) in spindle pole focusing; ASPM gene knockout alone does not disrupt spindle morphology, but ASPM KO combined with CDK5RAP2 depletion causes spindle pole unfocusing during prometaphase and delayed anaphase onset. A microcephaly-associated hypomorphic ASPM mutation similarly caused pole unfocusing only in the absence of CDK5RAP2.","method":"CRISPR-based gene knockout, auxin-inducible degron, siRNA, live-cell imaging","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — CRISPR KO plus inducible depletion system with defined spindle phenotype; genetic epistasis between ASPM and CDK5RAP2","pmids":["28883092"],"is_preprint":false},{"year":2018,"finding":"ASPM interacts with Disheveled-3 (Dvl-3), an upstream regulator of canonical Wnt signaling, and inhibits its proteasome-dependent degradation, thereby increasing Dvl-3 protein stability and enabling Wnt-induced β-catenin transcriptional activity in prostate cancer cells. ASPM depletion reduces ALDH+ cancer stem cell numbers and inhibits tumorigenicity.","method":"Co-immunoprecipitation, proteasome inhibitor rescue, siRNA knockdown, tumorigenicity assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with proteasome-inhibitor mechanistic rescue; multiple orthogonal methods","pmids":["30266990"],"is_preprint":false},{"year":2021,"finding":"ASPM is recruited to DNA double-strand break (DSB) sites in a PARP2-dependent manner. ASPM interacts with BRCA1 and its E3 ubiquitin ligase HERC2; ASPM prevents HERC2 from accessing BRCA1, thereby maintaining BRCA1 stability and enabling homologous recombination (HR) repair. ASPM inhibition promotes HERC2-mediated BRCA1 degradation, reduces HR efficiency, and sensitizes cells to ionizing radiation.","method":"Co-immunoprecipitation, PARP2 knockdown, HERC2 ubiquitination assay, HR repair assay, irradiation sensitivity","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 — Co-IP plus mechanistic ubiquitination and HR repair assays; multiple orthogonal methods","pmids":["34142045"],"is_preprint":false},{"year":2022,"finding":"ASPM is enriched at stalled replication forks in a RAD17-dependent manner and promotes RAD9 and TopBP1 loading onto chromatin, facilitating ATR-CHK1 checkpoint activation. ASPM depletion causes failed fork restart, MRE11-mediated nascent DNA degradation at stalled forks, chromosomal instability, and sensitization to replication stressors.","method":"iPOND (isolation of proteins on nascent DNA), chromatin fractionation, ATR-CHK1 phosphorylation assay, DNA fiber assay, siRNA knockdown","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple biochemical assays (iPOND, chromatin loading, fiber assay) establishing pathway position; strong mechanistic evidence","pmids":["36161901"],"is_preprint":false},{"year":2021,"finding":"ASPM combined with KIF11 promotes hepatocellular carcinoma progression via the Wnt/β-catenin signaling pathway. Co-immunoprecipitation demonstrated a direct interaction between ASPM and KIF11; KIF11 overexpression rescued the proliferation/invasion defects caused by ASPM knockdown.","method":"Co-immunoprecipitation, siRNA knockdown, rescue overexpression, Western blot for β-catenin pathway","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP plus rescue experiment; moderate mechanistic follow-up","pmids":["34504599"],"is_preprint":false},{"year":2011,"finding":"ASPM downregulation by siRNA impairs DNA double-strand break repair (as measured by constant-field gel electrophoresis and γ-H2AX foci) in human cell lines, and IR sensitization by ASPM knockdown is not enhanced in DNA-PK-deficient cells, indicating ASPM acts in a DNA-PK-dependent (NHEJ) pathway.","method":"siRNA knockdown, constant-field gel electrophoresis, γ-H2AX foci analysis, radiosensitivity assay in DNA-PK-deficient cells","journal":"International journal of radiation biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with DNA-PK-deficient cells plus DSB repair assays; single lab","pmids":["21923303"],"is_preprint":false},{"year":2021,"finding":"METTL3-mediated N6-methyladenosine (m6A) modification of ASPM mRNA promotes ASPM expression in hepatocellular carcinoma. MeRIP validated the m6A modification on ASPM mRNA; METTL3 silencing suppressed cell proliferation/invasion, which was rescued by ASPM overexpression.","method":"MeRIP (methylated RNA immunoprecipitation), siRNA knockdown, rescue overexpression","journal":"Journal of clinical laboratory analysis","confidence":"Medium","confidence_rationale":"Tier 3 — MeRIP plus rescue experiment; single lab, moderate mechanistic support","pmids":["34398984"],"is_preprint":false},{"year":2021,"finding":"In gastric cancer, ASPM isoform I (ASPMiI) interacts with DVL3 and together with FOXM1 controls β-catenin nuclear translocation and Wnt transcriptional activity through a multi-mode module: FOXM1 transcriptionally activates ASPM, ASPMiI stabilizes DVL3 via protein-protein interaction, and FOXM1 promotes β-catenin nuclear translocation.","method":"Co-immunoprecipitation, luciferase Wnt reporter, ChIP, siRNA knockdown, isoform-specific expression analysis","journal":"Gastric cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP, ChIP, and reporter assays; multiple methods but single lab","pmids":["33515163"],"is_preprint":false},{"year":2024,"finding":"RBM10 wild-type promotes ASPM exon 18 skipping by interacting with splicing factor SRSF2. RBM10 C761Y mutation impairs its interaction with SRSF2, generating the exon18-containing ASPM isoform (ASPM203) which stabilizes DVL2 and enhances β-catenin signaling to promote cholangiocarcinoma progression.","method":"Minigene splicing reporter, co-immunoprecipitation, RNA sequencing, siRNA/overexpression functional assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 — minigene splicing reporter plus Co-IP and signaling assays; multiple methods in single study","pmids":["38576051"],"is_preprint":false}],"current_model":"ASPM is a microtubule minus-end-associated protein that localizes to spindle poles via its C-terminus, where it cross-links microtubule minus ends to focus spindle poles, forms a complex with katanin to regulate spindle flux and microtubule disassembly, is phosphorylated by Polo kinase to enable centrosomal aster nucleation, and additionally functions in DNA damage responses by stabilizing BRCA1 (via blocking HERC2-mediated degradation), activating the ATR-CHK1 replication stress checkpoint, and regulating cell cycle progression through modulation of Cyclin E ubiquitination; in neural progenitors, ASPM also acts as a Wnt pathway co-activator by stabilizing Dvl-3 to promote β-catenin signaling and symmetric division, with loss-of-function mutations in ASPM causing primary microcephaly through defective progenitor proliferation."},"narrative":{"teleology":[{"year":2001,"claim":"The fundamental cellular role of ASPM at spindle poles was established: Drosophila Asp localizes to poles independently of centrosomes and is required for microtubule focusing into bipolar spindles and for central spindle organization, resolving whether this protein acts in microtubule nucleation versus pole organization.","evidence":"Genetic mutant analysis, immunofluorescence, epistasis with asterless, and colchicine treatment in Drosophila","pmids":["11352927"],"confidence":"High","gaps":["Mechanism of microtubule focusing by Asp (cross-linking vs. anchoring) not resolved","Whether vertebrate ASPM performs the identical function was untested","Regulation of Asp localization unknown"]},{"year":2001,"claim":"A regulatory input to ASPM was identified: Polo kinase phosphorylates Asp, and this phosphorylation is required together with γ-tubulin to reconstitute microtubule aster nucleation from stripped centrosomes, establishing a direct kinase-substrate relationship governing centrosome function.","evidence":"In vitro kinase assay, reciprocal co-immunoprecipitation, sucrose gradient sedimentation, and centrosome reconstitution assay in Drosophila embryo extracts","pmids":["11283617"],"confidence":"High","gaps":["Phosphorylation sites on Asp not mapped","Whether Polo regulation is conserved in mammalian ASPM unknown","How phosphorylation alters Asp biochemical activity not defined"]},{"year":2005,"claim":"Human ASPM was shown to localize to centrosomes/spindle poles throughout the cell cycle, and its depletion reduced BRCA1 protein levels, first linking ASPM to genome integrity pathways beyond spindle function.","evidence":"siRNA knockdown, immunofluorescence, and Western blot in human cells","pmids":["16123590"],"confidence":"Medium","gaps":["Mechanism by which ASPM stabilizes BRCA1 not identified","Whether BRCA1 reduction is a direct or indirect effect unknown","Functional consequence on DNA repair not tested"]},{"year":2007,"claim":"Domain mapping of ASPM revealed that its C-terminus mediates spindle pole and midbody localization and that all microcephaly-causing mutations truncate this region, connecting patient genetics to a specific protein domain; ASPM also interacts with citron kinase at the midbody, implicating it in cytokinesis.","evidence":"GFP-fragment localization, co-immunoprecipitation with citron kinase in HeLa and embryonic neuroepithelium","pmids":["17534152"],"confidence":"Medium","gaps":["Functional significance of the ASPM-citron kinase interaction not demonstrated by loss-of-function","Whether midbody function is separable from pole function untested"]},{"year":2010,"claim":"ASPM was established as a bona fide microtubule minus-end protein whose C-terminal domain is essential for spindle pole recruitment; a patient splice-site mutation disrupting this domain abolished pole localization and caused spindle/cytokinesis defects, directly linking the molecular defect to disease pathology.","evidence":"siRNA knockdown, live-cell imaging, patient fibroblast analysis, dominant-negative expression in U2OS cells","pmids":["21044324"],"confidence":"High","gaps":["Structural basis for minus-end recognition not resolved","Whether the dominant-negative effect reflects physiological stoichiometry not assessed"]},{"year":2011,"claim":"A non-mitotic role for ASPM emerged: it positively regulates Wnt/β-catenin signaling in the developing brain, and constitutively active β-catenin rescues cortical defects caused by Aspm knockdown, establishing that ASPM-dependent microcephaly involves defective Wnt-driven progenitor proliferation.","evidence":"In utero electroporation knockdown in mouse cortex, Wnt luciferase reporter, stabilized β-catenin rescue","pmids":["21937711"],"confidence":"High","gaps":["Direct binding partner in Wnt pathway not yet identified","Whether Wnt role is separable from spindle pole role unclear"]},{"year":2011,"claim":"ASPM was shown to participate in DNA double-strand break repair, acting in a DNA-PK-dependent (NHEJ) pathway, broadening its known functions to genome maintenance.","evidence":"siRNA knockdown, constant-field gel electrophoresis, γ-H2AX foci, epistasis with DNA-PK-deficient cells","pmids":["21923303"],"confidence":"Medium","gaps":["Mechanism of ASPM action in NHEJ not defined","Whether ASPM also contributes to HR not addressed","No structural or biochemical basis provided"]},{"year":2014,"claim":"The conserved functional partnership between ASPM and katanin was demonstrated: C. elegans ASPM-1 and the katanin MEI-1 are jointly required for meiotic spindle pole assembly, with katanin recruiting ASPM-1 to spindles, establishing evolutionary conservation of the ASPM-katanin axis.","evidence":"Temperature-sensitive alleles, live-cell imaging, and genetic epistasis in C. elegans oocyte meiosis","pmids":["24554763"],"confidence":"High","gaps":["Biochemical basis of ASPM-1–MEI-1 interaction not resolved","Whether mammalian ASPM-katanin interaction operates identically in meiosis untested"]},{"year":2015,"claim":"The biochemical mechanism of pole focusing was resolved: Drosophila Asp cross-links microtubule minus ends via a defined domain and focuses augmin-nucleated intraspindle microtubules during flux, independent of Ncd motor activity.","evidence":"In vitro microtubule cross-linking assay, RNAi depletion, live-cell imaging, domain analysis in Drosophila S2 cells","pmids":["26644514"],"confidence":"High","gaps":["Whether human ASPM has identical cross-linking activity in vitro not shown","Structural basis of the cross-linking domain not determined"]},{"year":2015,"claim":"ASPM was linked to G1 cell cycle control: it interacts with Cdk2/Cyclin E, modulates Cyclin E ubiquitination and nuclear translocation, and its mutation in mice leads to premature neural progenitor exhaustion due to shortened pre-restriction-point G1.","evidence":"ASPM knock-in mouse model, co-immunoprecipitation, ubiquitination assay, cell cycle analysis","pmids":["26581405"],"confidence":"High","gaps":["Whether ASPM directly inhibits the E3 ligase for Cyclin E or acts indirectly unclear","Relationship between Cyclin E regulation and Wnt signaling by ASPM not integrated"]},{"year":2017,"claim":"The molecular interface between ASPM and katanin was solved at atomic resolution, and reconstitution demonstrated that ASPM autonomously tracks growing microtubule minus ends, inhibits their growth, and cooperates with katanin to promote severing and regulate spindle flux—providing the most detailed mechanistic picture of ASPM's spindle function.","evidence":"X-ray crystallography of ASPM-katanin interface, TIRF-based in vitro reconstitution of minus-end tracking and severing, co-immunoprecipitation, siRNA in human cells","pmids":["28436967"],"confidence":"High","gaps":["Full-length ASPM structure unavailable","How disease-associated truncations alter the ASPM-katanin complex biochemically not tested in vitro","Regulation of the ASPM-katanin interaction during the cell cycle unknown"]},{"year":2017,"claim":"Genetic redundancy with CDK5RAP2 was revealed: ASPM knockout alone does not disrupt spindle morphology in human cells, but combined loss with CDK5RAP2 causes severe pole unfocusing, explaining the mild spindle phenotype in ASPM-null cells and highlighting compensatory mechanisms.","evidence":"CRISPR knockout, auxin-inducible degron depletion, siRNA, live-cell imaging in human cells","pmids":["28883092"],"confidence":"High","gaps":["Whether additional redundant factors exist is unknown","How CDK5RAP2 compensates mechanistically (independent minus-end focusing?) not resolved"]},{"year":2018,"claim":"The molecular basis for ASPM's Wnt co-activation was identified: ASPM binds Dishevelled-3 and prevents its proteasomal degradation, stabilizing Dvl-3 to enable β-catenin-dependent transcription, directly linking the earlier in vivo Wnt rescue finding to a specific protein interaction.","evidence":"Reciprocal co-immunoprecipitation, proteasome inhibitor rescue, siRNA knockdown, tumorigenicity assay in prostate cancer cells","pmids":["30266990"],"confidence":"High","gaps":["Whether ASPM also stabilizes Dvl-2 or other Dvl isoforms not tested","Structural basis of ASPM-Dvl-3 interaction unknown","Whether this mechanism operates in neural progenitors in vivo not confirmed"]},{"year":2021,"claim":"The mechanism of ASPM's BRCA1-stabilizing role in DNA repair was resolved: ASPM is recruited to DSBs in a PARP2-dependent manner and blocks HERC2-mediated ubiquitination and degradation of BRCA1, thereby enabling homologous recombination; this also reconciled the earlier finding on HR rather than NHEJ as the primary repair pathway affected.","evidence":"Co-immunoprecipitation, PARP2 knockdown, HERC2 ubiquitination assay, HR reporter assay, irradiation sensitivity in human cells","pmids":["34142045"],"confidence":"High","gaps":["Whether ASPM also promotes NHEJ as earlier suggested, or whether those findings reflected indirect effects via BRCA1, remains unclear","ASPM's role at DSBs versus replication forks not yet integrated"]},{"year":2022,"claim":"ASPM was found at stalled replication forks via RAD17-dependent recruitment, where it promotes RAD9/TopBP1 chromatin loading and ATR-CHK1 checkpoint activation; its loss causes fork degradation and chromosomal instability, establishing a replication stress checkpoint function distinct from its DSB repair role.","evidence":"iPOND, chromatin fractionation, ATR-CHK1 phosphorylation assay, DNA fiber assay, siRNA knockdown in human cells","pmids":["36161901"],"confidence":"High","gaps":["How ASPM structurally engages the 9-1-1 clamp loader complex unknown","Whether replication fork function contributes to microcephaly pathology not tested","Whether the spindle and DNA damage roles are coordinated across the cell cycle is unclear"]},{"year":2024,"claim":"Isoform-specific regulation of ASPM's Wnt function was uncovered: alternative splicing controlled by RBM10/SRSF2 determines inclusion of exon 18, generating an ASPM isoform that stabilizes DVL2 and enhances β-catenin signaling, revealing that splicing regulation diversifies ASPM's signaling output.","evidence":"Minigene splicing reporter, co-immunoprecipitation, RNA sequencing, functional assays in cholangiocarcinoma cells","pmids":["38576051"],"confidence":"Medium","gaps":["Whether exon 18-containing isoform differs in spindle function unknown","DVL2 versus DVL3 stabilization by different isoforms not systematically compared","In vivo relevance of isoform switching in brain development not addressed"]},{"year":null,"claim":"Key unresolved questions include how ASPM's spindle pole, Wnt signaling, and DNA damage/replication stress functions are coordinately regulated across the cell cycle; which functions are most critical for microcephaly pathogenesis; and what the full-length structure of ASPM looks like, particularly how disease-associated truncations alter its multiple interaction interfaces.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length structure of mammalian ASPM","Relative contributions of spindle, Wnt, and DNA damage functions to microcephaly not dissected in vivo","Cell-cycle-dependent regulation of ASPM's partitioning between chromatin and spindle unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,5,9,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,13,14,20]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,2,4,5,9,11,12]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,5,7,9,11]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[14,15]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,5,10,11,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,13,19,20]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[14,15,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,10]}],"complexes":["ASPM-katanin complex"],"partners":["KATNA1","KATNB1","DVL3","BRCA1","HERC2","CDK5RAP2","CCNE1","CITK"],"other_free_text":[]},"mechanistic_narrative":"ASPM is a microtubule minus-end-associated protein that focuses spindle poles, regulates DNA damage responses, and co-activates Wnt/β-catenin signaling, with loss-of-function mutations causing autosomal recessive primary microcephaly. At spindle poles, ASPM autonomously tracks growing microtubule minus ends, cross-links microtubule bundles to focus poles, and forms a complex with the katanin p60/p80 severing enzyme—resolved by crystallography—to regulate spindle flux and microtubule disassembly; it acts redundantly with CDK5RAP2 in pole focusing and requires Polo kinase phosphorylation for centrosomal aster nucleation [PMID:26644514, PMID:28436967, PMID:28883092, PMID:11283617]. Beyond the spindle, ASPM is recruited to DNA double-strand breaks in a PARP2-dependent manner where it stabilizes BRCA1 by blocking HERC2-mediated ubiquitination, and it localizes to stalled replication forks via RAD17 to promote RAD9/TopBP1 loading and ATR-CHK1 checkpoint activation [PMID:34142045, PMID:36161901]. In neural progenitors, ASPM modulates Cyclin E ubiquitination and Cdk2/Cyclin E-dependent G1 progression, and stabilizes Dishevelled-3 against proteasomal degradation to potentiate canonical Wnt/β-catenin transcriptional activity, thereby maintaining the proliferative symmetric division mode required for cortical expansion [PMID:26581405, PMID:21937711, PMID:30266990]."},"prefetch_data":{"uniprot":{"accession":"Q8IZT6","full_name":"Abnormal spindle-like microcephaly-associated protein","aliases":["Abnormal spindle protein homolog","Asp homolog"],"length_aa":3477,"mass_kda":409.8,"function":"Involved in mitotic spindle regulation and coordination of mitotic processes. The function in regulating microtubule dynamics at spindle poles including spindle orientation, astral microtubule density and poleward microtubule flux seems to depend on the association with the katanin complex formed by KATNA1 and KATNB1. Enhances the microtubule lattice severing activity of KATNA1 by recruiting the katanin complex to microtubules. Can block microtubule minus-end growth and reversely this function can be enhanced by the katanin complex (PubMed:28436967). May have a preferential role in regulating neurogenesis","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, spindle; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8IZT6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ASPM","classification":"Not Classified","n_dependent_lines":307,"n_total_lines":1208,"dependency_fraction":0.2541390728476821},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"HSPA4","stoichiometry":0.2},{"gene":"PSMA3","stoichiometry":0.2},{"gene":"PSMC5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ASPM","total_profiled":1310},"omim":[{"mim_id":"613583","title":"WD REPEAT-CONTAINING PROTEIN 62; WDR62","url":"https://www.omim.org/entry/613583"},{"mim_id":"612703","title":"MICROCEPHALY 7, PRIMARY, AUTOSOMAL RECESSIVE; MCPH7","url":"https://www.omim.org/entry/612703"},{"mim_id":"608716","title":"MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE; MCPH5","url":"https://www.omim.org/entry/608716"},{"mim_id":"607117","title":"MICROCEPHALIN 1; MCPH1","url":"https://www.omim.org/entry/607117"},{"mim_id":"605481","title":"ABNORMAL SPINDLE-LIKE, MICROCEPHALY-ASSOCIATED; ASPM","url":"https://www.omim.org/entry/605481"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":9.5},{"tissue":"lymphoid 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34504599","citation_count":16,"is_preprint":false},{"pmid":"36980263","id":"PMC_36980263","title":"The Multiple Mitotic Roles of the ASPM Orthologous Proteins: Insight into the Etiology of ASPM-Dependent Microcephaly.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36980263","citation_count":15,"is_preprint":false},{"pmid":"35997444","id":"PMC_35997444","title":"Anti-Inflammatory and Mineralization Effects of an ASP/PLGA-ASP/ACP/PLLA-PLGA Composite Membrane as a Dental Pulp Capping Agent.","date":"2022","source":"Journal of functional biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/35997444","citation_count":15,"is_preprint":false},{"pmid":"33156703","id":"PMC_33156703","title":"Australian snakebite myotoxicity (ASP-23).","date":"2020","source":"Clinical toxicology (Philadelphia, Pa.)","url":"https://pubmed.ncbi.nlm.nih.gov/33156703","citation_count":14,"is_preprint":false},{"pmid":"37428925","id":"PMC_37428925","title":"Horizontal gene transfer underlies the painful stings of asp caterpillars (Lepidoptera: Megalopygidae).","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37428925","citation_count":14,"is_preprint":false},{"pmid":"32117090","id":"PMC_32117090","title":"A Pilot Study of the Humoral Response Against the AntiSense Protein (ASP) in HIV-1-Infected Patients.","date":"2020","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32117090","citation_count":14,"is_preprint":false},{"pmid":"37599996","id":"PMC_37599996","title":"The neurological and non-neurological roles of the primary microcephaly-associated protein ASPM.","date":"2023","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37599996","citation_count":13,"is_preprint":false},{"pmid":"34067514","id":"PMC_34067514","title":"The HIV-1 Antisense Gene ASP: The New Kid on the Block.","date":"2021","source":"Vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/34067514","citation_count":13,"is_preprint":false},{"pmid":"32066665","id":"PMC_32066665","title":"A truncating Aspm allele leads to a complex cognitive phenotype and region-specific reductions in parvalbuminergic neurons.","date":"2020","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/32066665","citation_count":13,"is_preprint":false},{"pmid":"34229534","id":"PMC_34229534","title":"Angelica sinensis polysaccharide (ASP) attenuates diosbulbin-B (DB)-induced hepatotoxicity through activating the MEK/ERK pathway.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34229534","citation_count":12,"is_preprint":false},{"pmid":"20069551","id":"PMC_20069551","title":"Hormone and pharmaceutical regulation of ASP production in 3T3-L1 adipocytes.","date":"2010","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20069551","citation_count":12,"is_preprint":false},{"pmid":"11305044","id":"PMC_11305044","title":"[Cytotoxic activity and cytokine gene induction of Asp-hemolysin to vascular endothelial cells].","date":"2001","source":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","url":"https://pubmed.ncbi.nlm.nih.gov/11305044","citation_count":12,"is_preprint":false},{"pmid":"38576051","id":"PMC_38576051","title":"RBM10 C761Y mutation induced oncogenic ASPM isoforms and regulated β-catenin signaling in cholangiocarcinoma.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/38576051","citation_count":11,"is_preprint":false},{"pmid":"18792684","id":"PMC_18792684","title":"Dual regulation with Ser/Thr kinase cascade and a His/Asp TCS in Myxococcus xanthus.","date":"2008","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/18792684","citation_count":11,"is_preprint":false},{"pmid":"38191748","id":"PMC_38191748","title":"Caspase cleavage of RIPK3 after Asp333 is dispensable for mouse embryogenesis.","date":"2024","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/38191748","citation_count":11,"is_preprint":false},{"pmid":"17900365","id":"PMC_17900365","title":"Sensitive and reliable detection of Kit point mutation Asp 816 to Val in pathological material.","date":"2007","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/17900365","citation_count":11,"is_preprint":false},{"pmid":"28882889","id":"PMC_28882889","title":"The Rho ADP-ribosylating C3 exoenzyme binds cells via an Arg-Gly-Asp motif.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28882889","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48126,"output_tokens":5152,"usd":0.110829},"stage2":{"model":"claude-opus-4-6","input_tokens":8704,"output_tokens":4289,"usd":0.226117},"total_usd":0.336946,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Drosophila Asp (ASPM ortholog) is a 220-kDa microtubule-associated protein that localizes to spindle poles independently of functional centrosomes; in asp mutants, microtubule nucleation occurs normally but spindle pole focusing and central spindle organization are severely defective, leading to cytokinesis failure. Asp is required for aggregation of microtubules into focused spindle poles and for formation of the central spindle.\",\n      \"method\": \"Genetic mutant analysis (asp mutants), immunofluorescence, double mutant epistasis with asterless, colchicine treatment\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetics, imaging, epistasis) in single rigorous study; foundational Drosophila ortholog paper\",\n      \"pmids\": [\"11352927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Drosophila Asp is a substrate of Polo kinase; Polo phosphorylates Asp in vitro, generating an MPM2 epitope. Polo and Asp co-immunoprecipitate and exist in a 25–38S complex. Phosphorylated Asp is required (together with gamma-tubulin) to restore microtubule aster nucleation in salt-stripped centrosomes, and extracts from polo mutant embryos fail this rescue unless supplemented with phosphorylated Asp or active Polo kinase.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, sucrose gradient sedimentation, centrosome reconstitution assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro phosphorylation assay, reciprocal Co-IP, functional reconstitution; multiple orthogonal methods\",\n      \"pmids\": [\"11283617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human ASPM localizes to the centrosome during interphase and to spindle poles from prophase through telophase; siRNA-mediated downregulation of ASPM decreases endogenous BRCA1 protein levels, suggesting ASPM regulates BRCA1 at the centrosome/spindle pole.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, Western blot\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct localization by immunofluorescence tied to BRCA1 functional consequence; single lab, two methods\",\n      \"pmids\": [\"16123590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RNAi depletion of Drosophila Asp in S2 cells produces severe loss of spindle pole focus; Asp localizes to focused poles and is subtly mislocalized after dynein-dynactin depletion, indicating complex interdependence between dynein-dynactin, Asp, and KLP10A in spindle pole focusing and centrosome attachment.\",\n      \"method\": \"RNAi depletion, immunofluorescence, quantitative spindle analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi with defined cellular phenotype, epistasis-style analysis; single lab\",\n      \"pmids\": [\"15888542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human ASPM co-localizes with citron kinase (CITK) at the midbody ring during cytokinesis and co-immunoprecipitates with CITK from HeLa cell lysates and embryonic neuroepithelium. The N-terminal fragment of ASPM localizes to centrosomes/spindle poles, while the C-terminal fragment localizes to midbodies; all microcephaly-causing ASPM mutations truncate the C-terminus.\",\n      \"method\": \"Co-immunoprecipitation, GFP-fragment localization, immunofluorescence\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal Co-IP plus domain-mapping localization; moderate evidence from single lab\",\n      \"pmids\": [\"17534152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human ASPM is a microtubule minus-end-associated protein recruited in a microtubule-dependent manner to the pericentriolar matrix at spindle poles. siRNA depletion perturbs spindle orientation and causes cytokinesis failure in U2OS cells. A pathogenic splice-site mutation causing loss of a tripeptide from the C-terminus dramatically reduces ASPM spindle pole localization. Dominant-negative C-terminal ASPM fragments cause spindle assembly defects and cytokinesis failure.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, live-cell imaging, patient fibroblast analysis, dominant-negative expression\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD phenotype, patient mutation analysis, dominant-negative, localization studies) converging on spindle pole function\",\n      \"pmids\": [\"21044324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ASPM regulates Wnt signaling during brain development: Aspm knockdown in the developing mouse brain reduces Wnt-mediated transcription, and expression of stabilized β-catenin rescues both the signaling deficit and the in vivo cortical defects caused by Aspm knockdown.\",\n      \"method\": \"In utero electroporation knockdown, luciferase reporter assay, β-catenin rescue experiment\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knockdown with specific rescue by activated β-catenin; multiple complementary approaches\",\n      \"pmids\": [\"21937711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ASPM localizes to the entire spindle during mouse oocyte meiosis and co-localizes with acetylated tubulin. Morpholino-mediated knockdown causes elongated meiotic spindles and arrest at metaphase I. ASPM co-immunoprecipitates with calmodulin in metaphase I oocytes, and the two proteins co-localize at the spindle.\",\n      \"method\": \"Morpholino knockdown, immunofluorescence, co-immunoprecipitation, mass spectrometry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — morpholino KD with defined spindle phenotype plus Co-IP/MS identification of calmodulin interaction; single lab\",\n      \"pmids\": [\"23152892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In C. elegans, the calponin homology domain protein ASPM-1, together with the katanin MEI-1, is required for oocyte meiotic spindle pole assembly. MEI-1 recruits ASPM-1 to the spindle and also severs microtubules; both activities contribute to spindle bipolarity.\",\n      \"method\": \"Temperature-sensitive alleles, live-cell imaging, genetic epistasis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live imaging with temperature-sensitive alleles and epistasis; ortholog study in C. elegans\",\n      \"pmids\": [\"24554763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Drosophila Asp localizes to minus ends of spindle microtubule bundles and focuses them at poles independent of Ncd. An identified domain in Asp has microtubule cross-linking activity in vitro. Asp also localizes to minus ends of intraspindle augmin-dependent microtubules and focuses them toward poles during spindle flux.\",\n      \"method\": \"In vitro microtubule cross-linking assay, RNAi depletion, live-cell imaging, domain analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro MT cross-linking reconstitution plus live imaging of minus-end dynamics; multiple orthogonal methods\",\n      \"pmids\": [\"26644514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ASPM interacts with the Cdk2/Cyclin E complex and modulates Cyclin E ubiquitination and phosphorylation, thereby regulating nuclear translocation of Cyclin E and the timing of restriction point passage in neural progenitors. ASPM-mutant mice show premature neural progenitor pool exhaustion due to shortened G1 before the restriction point.\",\n      \"method\": \"ASPM knock-in mouse model, co-immunoprecipitation, ubiquitination assay, cell cycle analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mouse model plus Co-IP and ubiquitination assay; multiple orthogonal methods establishing the Cdk2/Cyclin E interaction\",\n      \"pmids\": [\"26581405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ASPM forms a complex with the microtubule-severing ATPase katanin (p60/p80 heterodimer). X-ray crystallography revealed that the N- and C-terminal domains of katanin p60 and p80, respectively, bind conserved motifs in ASPM. Reconstitution experiments showed ASPM autonomously tracks growing microtubule minus ends and inhibits their growth; katanin potentiates this minus-end blocking and, together with ASPM, promotes microtubule severing. ASPM and katanin localize to spindle poles in a mutually dependent manner and regulate spindle flux.\",\n      \"method\": \"X-ray crystallography, in vitro microtubule reconstitution, TIRF microscopy, co-immunoprecipitation, siRNA knockdown\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of ASPM-katanin interface, in vitro reconstitution of minus-end tracking and severing, multiple orthogonal methods in single study\",\n      \"pmids\": [\"28436967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human ASPM functions redundantly with CDK5RAP2 (CEP215) in spindle pole focusing; ASPM gene knockout alone does not disrupt spindle morphology, but ASPM KO combined with CDK5RAP2 depletion causes spindle pole unfocusing during prometaphase and delayed anaphase onset. A microcephaly-associated hypomorphic ASPM mutation similarly caused pole unfocusing only in the absence of CDK5RAP2.\",\n      \"method\": \"CRISPR-based gene knockout, auxin-inducible degron, siRNA, live-cell imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO plus inducible depletion system with defined spindle phenotype; genetic epistasis between ASPM and CDK5RAP2\",\n      \"pmids\": [\"28883092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ASPM interacts with Disheveled-3 (Dvl-3), an upstream regulator of canonical Wnt signaling, and inhibits its proteasome-dependent degradation, thereby increasing Dvl-3 protein stability and enabling Wnt-induced β-catenin transcriptional activity in prostate cancer cells. ASPM depletion reduces ALDH+ cancer stem cell numbers and inhibits tumorigenicity.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor rescue, siRNA knockdown, tumorigenicity assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with proteasome-inhibitor mechanistic rescue; multiple orthogonal methods\",\n      \"pmids\": [\"30266990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ASPM is recruited to DNA double-strand break (DSB) sites in a PARP2-dependent manner. ASPM interacts with BRCA1 and its E3 ubiquitin ligase HERC2; ASPM prevents HERC2 from accessing BRCA1, thereby maintaining BRCA1 stability and enabling homologous recombination (HR) repair. ASPM inhibition promotes HERC2-mediated BRCA1 degradation, reduces HR efficiency, and sensitizes cells to ionizing radiation.\",\n      \"method\": \"Co-immunoprecipitation, PARP2 knockdown, HERC2 ubiquitination assay, HR repair assay, irradiation sensitivity\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus mechanistic ubiquitination and HR repair assays; multiple orthogonal methods\",\n      \"pmids\": [\"34142045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ASPM is enriched at stalled replication forks in a RAD17-dependent manner and promotes RAD9 and TopBP1 loading onto chromatin, facilitating ATR-CHK1 checkpoint activation. ASPM depletion causes failed fork restart, MRE11-mediated nascent DNA degradation at stalled forks, chromosomal instability, and sensitization to replication stressors.\",\n      \"method\": \"iPOND (isolation of proteins on nascent DNA), chromatin fractionation, ATR-CHK1 phosphorylation assay, DNA fiber assay, siRNA knockdown\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical assays (iPOND, chromatin loading, fiber assay) establishing pathway position; strong mechanistic evidence\",\n      \"pmids\": [\"36161901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ASPM combined with KIF11 promotes hepatocellular carcinoma progression via the Wnt/β-catenin signaling pathway. Co-immunoprecipitation demonstrated a direct interaction between ASPM and KIF11; KIF11 overexpression rescued the proliferation/invasion defects caused by ASPM knockdown.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, rescue overexpression, Western blot for β-catenin pathway\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus rescue experiment; moderate mechanistic follow-up\",\n      \"pmids\": [\"34504599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ASPM downregulation by siRNA impairs DNA double-strand break repair (as measured by constant-field gel electrophoresis and γ-H2AX foci) in human cell lines, and IR sensitization by ASPM knockdown is not enhanced in DNA-PK-deficient cells, indicating ASPM acts in a DNA-PK-dependent (NHEJ) pathway.\",\n      \"method\": \"siRNA knockdown, constant-field gel electrophoresis, γ-H2AX foci analysis, radiosensitivity assay in DNA-PK-deficient cells\",\n      \"journal\": \"International journal of radiation biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with DNA-PK-deficient cells plus DSB repair assays; single lab\",\n      \"pmids\": [\"21923303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"METTL3-mediated N6-methyladenosine (m6A) modification of ASPM mRNA promotes ASPM expression in hepatocellular carcinoma. MeRIP validated the m6A modification on ASPM mRNA; METTL3 silencing suppressed cell proliferation/invasion, which was rescued by ASPM overexpression.\",\n      \"method\": \"MeRIP (methylated RNA immunoprecipitation), siRNA knockdown, rescue overexpression\",\n      \"journal\": \"Journal of clinical laboratory analysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — MeRIP plus rescue experiment; single lab, moderate mechanistic support\",\n      \"pmids\": [\"34398984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In gastric cancer, ASPM isoform I (ASPMiI) interacts with DVL3 and together with FOXM1 controls β-catenin nuclear translocation and Wnt transcriptional activity through a multi-mode module: FOXM1 transcriptionally activates ASPM, ASPMiI stabilizes DVL3 via protein-protein interaction, and FOXM1 promotes β-catenin nuclear translocation.\",\n      \"method\": \"Co-immunoprecipitation, luciferase Wnt reporter, ChIP, siRNA knockdown, isoform-specific expression analysis\",\n      \"journal\": \"Gastric cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP, ChIP, and reporter assays; multiple methods but single lab\",\n      \"pmids\": [\"33515163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM10 wild-type promotes ASPM exon 18 skipping by interacting with splicing factor SRSF2. RBM10 C761Y mutation impairs its interaction with SRSF2, generating the exon18-containing ASPM isoform (ASPM203) which stabilizes DVL2 and enhances β-catenin signaling to promote cholangiocarcinoma progression.\",\n      \"method\": \"Minigene splicing reporter, co-immunoprecipitation, RNA sequencing, siRNA/overexpression functional assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — minigene splicing reporter plus Co-IP and signaling assays; multiple methods in single study\",\n      \"pmids\": [\"38576051\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ASPM is a microtubule minus-end-associated protein that localizes to spindle poles via its C-terminus, where it cross-links microtubule minus ends to focus spindle poles, forms a complex with katanin to regulate spindle flux and microtubule disassembly, is phosphorylated by Polo kinase to enable centrosomal aster nucleation, and additionally functions in DNA damage responses by stabilizing BRCA1 (via blocking HERC2-mediated degradation), activating the ATR-CHK1 replication stress checkpoint, and regulating cell cycle progression through modulation of Cyclin E ubiquitination; in neural progenitors, ASPM also acts as a Wnt pathway co-activator by stabilizing Dvl-3 to promote β-catenin signaling and symmetric division, with loss-of-function mutations in ASPM causing primary microcephaly through defective progenitor proliferation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ASPM is a microtubule minus-end-associated protein that focuses spindle poles, regulates DNA damage responses, and co-activates Wnt/β-catenin signaling, with loss-of-function mutations causing autosomal recessive primary microcephaly. At spindle poles, ASPM autonomously tracks growing microtubule minus ends, cross-links microtubule bundles to focus poles, and forms a complex with the katanin p60/p80 severing enzyme—resolved by crystallography—to regulate spindle flux and microtubule disassembly; it acts redundantly with CDK5RAP2 in pole focusing and requires Polo kinase phosphorylation for centrosomal aster nucleation [PMID:26644514, PMID:28436967, PMID:28883092, PMID:11283617]. Beyond the spindle, ASPM is recruited to DNA double-strand breaks in a PARP2-dependent manner where it stabilizes BRCA1 by blocking HERC2-mediated ubiquitination, and it localizes to stalled replication forks via RAD17 to promote RAD9/TopBP1 loading and ATR-CHK1 checkpoint activation [PMID:34142045, PMID:36161901]. In neural progenitors, ASPM modulates Cyclin E ubiquitination and Cdk2/Cyclin E-dependent G1 progression, and stabilizes Dishevelled-3 against proteasomal degradation to potentiate canonical Wnt/β-catenin transcriptional activity, thereby maintaining the proliferative symmetric division mode required for cortical expansion [PMID:26581405, PMID:21937711, PMID:30266990].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"The fundamental cellular role of ASPM at spindle poles was established: Drosophila Asp localizes to poles independently of centrosomes and is required for microtubule focusing into bipolar spindles and for central spindle organization, resolving whether this protein acts in microtubule nucleation versus pole organization.\",\n      \"evidence\": \"Genetic mutant analysis, immunofluorescence, epistasis with asterless, and colchicine treatment in Drosophila\",\n      \"pmids\": [\"11352927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of microtubule focusing by Asp (cross-linking vs. anchoring) not resolved\", \"Whether vertebrate ASPM performs the identical function was untested\", \"Regulation of Asp localization unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"A regulatory input to ASPM was identified: Polo kinase phosphorylates Asp, and this phosphorylation is required together with γ-tubulin to reconstitute microtubule aster nucleation from stripped centrosomes, establishing a direct kinase-substrate relationship governing centrosome function.\",\n      \"evidence\": \"In vitro kinase assay, reciprocal co-immunoprecipitation, sucrose gradient sedimentation, and centrosome reconstitution assay in Drosophila embryo extracts\",\n      \"pmids\": [\"11283617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation sites on Asp not mapped\", \"Whether Polo regulation is conserved in mammalian ASPM unknown\", \"How phosphorylation alters Asp biochemical activity not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Human ASPM was shown to localize to centrosomes/spindle poles throughout the cell cycle, and its depletion reduced BRCA1 protein levels, first linking ASPM to genome integrity pathways beyond spindle function.\",\n      \"evidence\": \"siRNA knockdown, immunofluorescence, and Western blot in human cells\",\n      \"pmids\": [\"16123590\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ASPM stabilizes BRCA1 not identified\", \"Whether BRCA1 reduction is a direct or indirect effect unknown\", \"Functional consequence on DNA repair not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Domain mapping of ASPM revealed that its C-terminus mediates spindle pole and midbody localization and that all microcephaly-causing mutations truncate this region, connecting patient genetics to a specific protein domain; ASPM also interacts with citron kinase at the midbody, implicating it in cytokinesis.\",\n      \"evidence\": \"GFP-fragment localization, co-immunoprecipitation with citron kinase in HeLa and embryonic neuroepithelium\",\n      \"pmids\": [\"17534152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of the ASPM-citron kinase interaction not demonstrated by loss-of-function\", \"Whether midbody function is separable from pole function untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"ASPM was established as a bona fide microtubule minus-end protein whose C-terminal domain is essential for spindle pole recruitment; a patient splice-site mutation disrupting this domain abolished pole localization and caused spindle/cytokinesis defects, directly linking the molecular defect to disease pathology.\",\n      \"evidence\": \"siRNA knockdown, live-cell imaging, patient fibroblast analysis, dominant-negative expression in U2OS cells\",\n      \"pmids\": [\"21044324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for minus-end recognition not resolved\", \"Whether the dominant-negative effect reflects physiological stoichiometry not assessed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"A non-mitotic role for ASPM emerged: it positively regulates Wnt/β-catenin signaling in the developing brain, and constitutively active β-catenin rescues cortical defects caused by Aspm knockdown, establishing that ASPM-dependent microcephaly involves defective Wnt-driven progenitor proliferation.\",\n      \"evidence\": \"In utero electroporation knockdown in mouse cortex, Wnt luciferase reporter, stabilized β-catenin rescue\",\n      \"pmids\": [\"21937711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partner in Wnt pathway not yet identified\", \"Whether Wnt role is separable from spindle pole role unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"ASPM was shown to participate in DNA double-strand break repair, acting in a DNA-PK-dependent (NHEJ) pathway, broadening its known functions to genome maintenance.\",\n      \"evidence\": \"siRNA knockdown, constant-field gel electrophoresis, γ-H2AX foci, epistasis with DNA-PK-deficient cells\",\n      \"pmids\": [\"21923303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ASPM action in NHEJ not defined\", \"Whether ASPM also contributes to HR not addressed\", \"No structural or biochemical basis provided\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The conserved functional partnership between ASPM and katanin was demonstrated: C. elegans ASPM-1 and the katanin MEI-1 are jointly required for meiotic spindle pole assembly, with katanin recruiting ASPM-1 to spindles, establishing evolutionary conservation of the ASPM-katanin axis.\",\n      \"evidence\": \"Temperature-sensitive alleles, live-cell imaging, and genetic epistasis in C. elegans oocyte meiosis\",\n      \"pmids\": [\"24554763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical basis of ASPM-1–MEI-1 interaction not resolved\", \"Whether mammalian ASPM-katanin interaction operates identically in meiosis untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The biochemical mechanism of pole focusing was resolved: Drosophila Asp cross-links microtubule minus ends via a defined domain and focuses augmin-nucleated intraspindle microtubules during flux, independent of Ncd motor activity.\",\n      \"evidence\": \"In vitro microtubule cross-linking assay, RNAi depletion, live-cell imaging, domain analysis in Drosophila S2 cells\",\n      \"pmids\": [\"26644514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether human ASPM has identical cross-linking activity in vitro not shown\", \"Structural basis of the cross-linking domain not determined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"ASPM was linked to G1 cell cycle control: it interacts with Cdk2/Cyclin E, modulates Cyclin E ubiquitination and nuclear translocation, and its mutation in mice leads to premature neural progenitor exhaustion due to shortened pre-restriction-point G1.\",\n      \"evidence\": \"ASPM knock-in mouse model, co-immunoprecipitation, ubiquitination assay, cell cycle analysis\",\n      \"pmids\": [\"26581405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ASPM directly inhibits the E3 ligase for Cyclin E or acts indirectly unclear\", \"Relationship between Cyclin E regulation and Wnt signaling by ASPM not integrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The molecular interface between ASPM and katanin was solved at atomic resolution, and reconstitution demonstrated that ASPM autonomously tracks growing microtubule minus ends, inhibits their growth, and cooperates with katanin to promote severing and regulate spindle flux—providing the most detailed mechanistic picture of ASPM's spindle function.\",\n      \"evidence\": \"X-ray crystallography of ASPM-katanin interface, TIRF-based in vitro reconstitution of minus-end tracking and severing, co-immunoprecipitation, siRNA in human cells\",\n      \"pmids\": [\"28436967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length ASPM structure unavailable\", \"How disease-associated truncations alter the ASPM-katanin complex biochemically not tested in vitro\", \"Regulation of the ASPM-katanin interaction during the cell cycle unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetic redundancy with CDK5RAP2 was revealed: ASPM knockout alone does not disrupt spindle morphology in human cells, but combined loss with CDK5RAP2 causes severe pole unfocusing, explaining the mild spindle phenotype in ASPM-null cells and highlighting compensatory mechanisms.\",\n      \"evidence\": \"CRISPR knockout, auxin-inducible degron depletion, siRNA, live-cell imaging in human cells\",\n      \"pmids\": [\"28883092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional redundant factors exist is unknown\", \"How CDK5RAP2 compensates mechanistically (independent minus-end focusing?) not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The molecular basis for ASPM's Wnt co-activation was identified: ASPM binds Dishevelled-3 and prevents its proteasomal degradation, stabilizing Dvl-3 to enable β-catenin-dependent transcription, directly linking the earlier in vivo Wnt rescue finding to a specific protein interaction.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, proteasome inhibitor rescue, siRNA knockdown, tumorigenicity assay in prostate cancer cells\",\n      \"pmids\": [\"30266990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ASPM also stabilizes Dvl-2 or other Dvl isoforms not tested\", \"Structural basis of ASPM-Dvl-3 interaction unknown\", \"Whether this mechanism operates in neural progenitors in vivo not confirmed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The mechanism of ASPM's BRCA1-stabilizing role in DNA repair was resolved: ASPM is recruited to DSBs in a PARP2-dependent manner and blocks HERC2-mediated ubiquitination and degradation of BRCA1, thereby enabling homologous recombination; this also reconciled the earlier finding on HR rather than NHEJ as the primary repair pathway affected.\",\n      \"evidence\": \"Co-immunoprecipitation, PARP2 knockdown, HERC2 ubiquitination assay, HR reporter assay, irradiation sensitivity in human cells\",\n      \"pmids\": [\"34142045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ASPM also promotes NHEJ as earlier suggested, or whether those findings reflected indirect effects via BRCA1, remains unclear\", \"ASPM's role at DSBs versus replication forks not yet integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ASPM was found at stalled replication forks via RAD17-dependent recruitment, where it promotes RAD9/TopBP1 chromatin loading and ATR-CHK1 checkpoint activation; its loss causes fork degradation and chromosomal instability, establishing a replication stress checkpoint function distinct from its DSB repair role.\",\n      \"evidence\": \"iPOND, chromatin fractionation, ATR-CHK1 phosphorylation assay, DNA fiber assay, siRNA knockdown in human cells\",\n      \"pmids\": [\"36161901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ASPM structurally engages the 9-1-1 clamp loader complex unknown\", \"Whether replication fork function contributes to microcephaly pathology not tested\", \"Whether the spindle and DNA damage roles are coordinated across the cell cycle is unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Isoform-specific regulation of ASPM's Wnt function was uncovered: alternative splicing controlled by RBM10/SRSF2 determines inclusion of exon 18, generating an ASPM isoform that stabilizes DVL2 and enhances β-catenin signaling, revealing that splicing regulation diversifies ASPM's signaling output.\",\n      \"evidence\": \"Minigene splicing reporter, co-immunoprecipitation, RNA sequencing, functional assays in cholangiocarcinoma cells\",\n      \"pmids\": [\"38576051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether exon 18-containing isoform differs in spindle function unknown\", \"DVL2 versus DVL3 stabilization by different isoforms not systematically compared\", \"In vivo relevance of isoform switching in brain development not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how ASPM's spindle pole, Wnt signaling, and DNA damage/replication stress functions are coordinately regulated across the cell cycle; which functions are most critical for microcephaly pathogenesis; and what the full-length structure of ASPM looks like, particularly how disease-associated truncations alter its multiple interaction interfaces.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length structure of mammalian ASPM\", \"Relative contributions of spindle, Wnt, and DNA damage functions to microcephaly not dissected in vivo\", \"Cell-cycle-dependent regulation of ASPM's partitioning between chromatin and spindle unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 5, 9, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 13, 14, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 2, 4, 5, 9, 11, 12]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 5, 7, 9, 11]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [14, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 5, 10, 11, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 13, 19, 20]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [14, 15, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"complexes\": [\n      \"ASPM-katanin complex\"\n    ],\n    \"partners\": [\n      \"KATNA1\",\n      \"KATNB1\",\n      \"DVL3\",\n      \"BRCA1\",\n      \"HERC2\",\n      \"CDK5RAP2\",\n      \"CCNE1\",\n      \"CITK\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}