{"gene":"CLSPN","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2020,"finding":"A CLSPN variant (c.1574A>G; p.Asn525Ser) causes partial exon skipping and decreased Claspin expression, resulting in reduced CHK1 activation, as demonstrated by minigene splicing assay and signaling experiments.","method":"Minigene splicing assay, western blot/signaling experiments","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (minigene assay + signaling experiments) in a single study establishing functional impact of variant on CHK1 activation","pmids":["32847043"],"is_preprint":false},{"year":2020,"finding":"A CLSPN promoter variant (c.-68C>T) increases CLSPN transcriptional activity, as demonstrated by luciferase reporter assay.","method":"Luciferase reporter assay","journal":"Cancers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (luciferase assay), single lab, no functional follow-up","pmids":["32847043"],"is_preprint":false},{"year":2024,"finding":"CLSPN overexpression promotes glycolysis and cell proliferation in oral squamous cell carcinoma via activation of the Wnt/β-catenin signaling pathway; knockdown of Wnt3a reversed the pro-glycolytic and pro-proliferative effects of CLSPN overexpression.","method":"Overexpression/knockdown experiments, ECAR/OCR metabolic assays, western blot, in vivo xenograft, rescue experiments with Wnt3a knockdown","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple phenotypic assays and rescue experiment establishing pathway placement, but mechanism connecting Claspin to Wnt/β-catenin is not biochemically resolved","pmids":["38237848"],"is_preprint":false},{"year":2025,"finding":"ALKBH5-mediated m6A demethylation reduces CLSPN mRNA stability in an IGF2BP2-dependent manner; low ALKBH5 leads to IGF2BP2-dependent stabilization of CLSPN mRNA, promoting docetaxel resistance in prostate cancer.","method":"Multi-omics analysis, overexpression/knockdown experiments, organoid models, clinical sample validation","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics plus functional rescue experiments in multiple models establishing the ALKBH5-IGF2BP2-CLSPN mRNA stability axis, single lab","pmids":["41069850"],"is_preprint":false}],"current_model":"Claspin (CLSPN) functions as a DNA replication stress sensor that activates CHK1 (with loss-of-function variants reducing CHK1 phosphorylation), and its expression is post-transcriptionally regulated by m6A methylation via the ALKBH5/IGF2BP2 axis that controls CLSPN mRNA stability; additionally, Claspin overexpression can activate Wnt/β-catenin signaling to promote glycolysis and cell proliferation, though the biochemical mechanism linking Claspin to Wnt signaling remains unresolved."},"narrative":{"mechanistic_narrative":"Claspin (CLSPN) functions in the DNA replication stress response, where it is required for activation of the checkpoint kinase CHK1: a coding variant that causes partial exon skipping and reduced Claspin expression correspondingly diminishes CHK1 activation [PMID:32847043]. Beyond this checkpoint role, CLSPN expression is controlled post-transcriptionally through m6A regulation, whereby ALKBH5-mediated demethylation destabilizes CLSPN mRNA in an IGF2BP2-dependent manner, such that low ALKBH5 permits IGF2BP2-dependent stabilization of the transcript and drives docetaxel resistance in prostate cancer [PMID:41069850]. In oral squamous cell carcinoma, CLSPN overexpression promotes glycolysis and proliferation through activation of Wnt/β-catenin signaling, with Wnt3a knockdown reversing these effects [PMID:38237848], although the biochemical link between Claspin and Wnt signaling is not resolved in the available corpus.","teleology":[{"year":2020,"claim":"Established that Claspin abundance is rate-limiting for CHK1 checkpoint activation by showing a splice-affecting coding variant reduces both Claspin expression and CHK1 phosphorylation.","evidence":"Minigene splicing assay and signaling/western blot experiments for the c.1574A>G (p.Asn525Ser) variant","pmids":["32847043"],"confidence":"Medium","gaps":["Does not define the biochemical mechanism by which Claspin activates CHK1","Single study; effect of variant on patient phenotype not established","No structural characterization of the variant residue"]},{"year":2020,"claim":"Identified a promoter variant that elevates CLSPN transcription, indicating transcriptional regulation of Claspin levels.","evidence":"Luciferase reporter assay for the c.-68C>T promoter variant","pmids":["32847043"],"confidence":"Low","gaps":["Single method (luciferase) without functional follow-up","Transcription factor responsible not identified","No link to downstream CHK1 or phenotype"]},{"year":2024,"claim":"Placed CLSPN upstream of Wnt/β-catenin signaling in cancer metabolism by showing its overexpression drives glycolysis and proliferation in a Wnt3a-dependent manner.","evidence":"Overexpression/knockdown, ECAR/OCR metabolic assays, xenografts, and Wnt3a-knockdown rescue in oral squamous cell carcinoma","pmids":["38237848"],"confidence":"Medium","gaps":["Biochemical mechanism connecting Claspin to Wnt/β-catenin not resolved","Relationship to Claspin's canonical checkpoint role unclear","No direct physical partner in the Wnt pathway identified"]},{"year":2025,"claim":"Defined post-transcriptional control of CLSPN through an m6A axis, explaining how its mRNA stability is tuned and links it to chemotherapy resistance.","evidence":"Multi-omics, knockdown/overexpression, organoid models, and clinical samples establishing the ALKBH5–IGF2BP2–CLSPN mRNA stability axis in prostate cancer","pmids":["41069850"],"confidence":"Medium","gaps":["m6A site(s) on CLSPN mRNA not mapped","Single lab; mechanism of IGF2BP2-dependent stabilization not biochemically dissected","Connection between altered CLSPN levels and the checkpoint/Wnt functions not integrated"]},{"year":null,"claim":"The biochemical mechanism by which Claspin engages CHK1 and Wnt/β-catenin signaling, and how its post-transcriptional regulation integrates with these functions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or domain-level mechanism for CHK1 activation in the corpus","Direct molecular link between Claspin and Wnt/β-catenin unknown","No reported direct physical interactors of Claspin in the timeline"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HAW4","full_name":"Claspin","aliases":[],"length_aa":1339,"mass_kda":151.1,"function":"Required for checkpoint mediated cell cycle arrest in response to inhibition of DNA replication or to DNA damage induced by both ionizing and UV irradiation (PubMed:12766152, PubMed:15190204, PubMed:15707391, PubMed:16123041). Adapter protein which binds to BRCA1 and the checkpoint kinase CHEK1 and facilitates the ATR-dependent phosphorylation of both proteins (PubMed:12766152, PubMed:15096610, PubMed:15707391, PubMed:16123041). Also required to maintain normal rates of replication fork progression during unperturbed DNA replication. Binds directly to DNA, with particular affinity for branched or forked molecules and interacts with multiple protein components of the replisome such as the MCM2-7 complex and TIMELESS (PubMed:15226314, PubMed:34694004, PubMed:35585232). Important for initiation of DNA replication, recruits kinase CDC7 to phosphorylate MCM2-7 components (PubMed:27401717)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9HAW4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CLSPN","classification":"Common Essential","n_dependent_lines":1004,"n_total_lines":1208,"dependency_fraction":0.8311258278145696},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2},{"gene":"SRP14","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CLSPN","total_profiled":1310},"omim":[{"mim_id":"620302","title":"WD REPEAT-CONTAINING PROTEIN 76; WDR76","url":"https://www.omim.org/entry/620302"},{"mim_id":"610716","title":"TIMELESS-INTERACTING PROTEIN; TIPIN","url":"https://www.omim.org/entry/610716"},{"mim_id":"605434","title":"CLASPIN; CLSPN","url":"https://www.omim.org/entry/605434"},{"mim_id":"603887","title":"TIMELESS CIRCADIAN REGULATOR; TIMELESS","url":"https://www.omim.org/entry/603887"},{"mim_id":"603482","title":"BETA-TRANSDUCIN REPEAT-CONTAINING PROTEIN; BTRC","url":"https://www.omim.org/entry/603482"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Golgi apparatus","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":10.6},{"tissue":"lymphoid tissue","ntpm":7.3},{"tissue":"retina","ntpm":6.3},{"tissue":"testis","ntpm":5.4}],"url":"https://www.proteinatlas.org/search/CLSPN"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9HAW4","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HAW4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HAW4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HAW4-F1-predicted_aligned_error_v6.png","plddt_mean":50.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CLSPN","jax_strain_url":"https://www.jax.org/strain/search?query=CLSPN"},"sequence":{"accession":"Q9HAW4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HAW4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HAW4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HAW4"}},"corpus_meta":[{"pmid":"18077083","id":"PMC_18077083","title":"Germline alterations in the CLSPN gene in breast cancer families.","date":"2008","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/18077083","citation_count":13,"is_preprint":false},{"pmid":"38237848","id":"PMC_38237848","title":"CLSPN actives Wnt/β-catenin signaling to facilitate glycolysis and cell proliferation in oral squamous cell carcinoma.","date":"2024","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/38237848","citation_count":11,"is_preprint":false},{"pmid":"34269180","id":"PMC_34269180","title":"circRNA derived from CLSPN (circCLSPN) is an oncogene in human glioblastoma multiforme by regulating cell growth, migration and invasion via ceRNA pathway.","date":"2021","source":"Journal of biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/34269180","citation_count":10,"is_preprint":false},{"pmid":"32847043","id":"PMC_32847043","title":"Implications of CLSPN Variants in Cellular Function and Susceptibility to Cancer.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32847043","citation_count":6,"is_preprint":false},{"pmid":"41069850","id":"PMC_41069850","title":"ALKBH5-IGF2BP2 axis mediates prostate cancer progression and docetaxel resistance via m6A-stabilized CLSPN RNA.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41069850","citation_count":3,"is_preprint":false},{"pmid":"38256171","id":"PMC_38256171","title":"The Interaction between CLSPN Gene Polymorphisms and Alcohol Consumption Contributes to Oral Cancer Progression.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38256171","citation_count":3,"is_preprint":false},{"pmid":"40275302","id":"PMC_40275302","title":"Potential of CLSPN as a therapeutic target in melanoma: a key player in melanoma progression and tumor microenvironment.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40275302","citation_count":1,"is_preprint":false},{"pmid":"39539024","id":"PMC_39539024","title":"Establishment of potent TCR-T cells specific for cisplatin-resistance related tumor-associated antigen, CLSPN using codon-optimization.","date":"2024","source":"Human vaccines & immunotherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/39539024","citation_count":0,"is_preprint":false},{"pmid":"41656416","id":"PMC_41656416","title":"Integrating multi-omics analysis identifies DNA damage-related gene CLSPN as a biomarker in gastric cancer.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41656416","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6778,"output_tokens":948,"usd":0.017277,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7452,"output_tokens":1753,"usd":0.040543,"stage2_stop_reason":"end_turn"},"total_usd":0.05782,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"A CLSPN variant (c.1574A>G; p.Asn525Ser) causes partial exon skipping and decreased Claspin expression, resulting in reduced CHK1 activation, as demonstrated by minigene splicing assay and signaling experiments.\",\n      \"method\": \"Minigene splicing assay, western blot/signaling experiments\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (minigene assay + signaling experiments) in a single study establishing functional impact of variant on CHK1 activation\",\n      \"pmids\": [\"32847043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A CLSPN promoter variant (c.-68C>T) increases CLSPN transcriptional activity, as demonstrated by luciferase reporter assay.\",\n      \"method\": \"Luciferase reporter assay\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (luciferase assay), single lab, no functional follow-up\",\n      \"pmids\": [\"32847043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CLSPN overexpression promotes glycolysis and cell proliferation in oral squamous cell carcinoma via activation of the Wnt/β-catenin signaling pathway; knockdown of Wnt3a reversed the pro-glycolytic and pro-proliferative effects of CLSPN overexpression.\",\n      \"method\": \"Overexpression/knockdown experiments, ECAR/OCR metabolic assays, western blot, in vivo xenograft, rescue experiments with Wnt3a knockdown\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple phenotypic assays and rescue experiment establishing pathway placement, but mechanism connecting Claspin to Wnt/β-catenin is not biochemically resolved\",\n      \"pmids\": [\"38237848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ALKBH5-mediated m6A demethylation reduces CLSPN mRNA stability in an IGF2BP2-dependent manner; low ALKBH5 leads to IGF2BP2-dependent stabilization of CLSPN mRNA, promoting docetaxel resistance in prostate cancer.\",\n      \"method\": \"Multi-omics analysis, overexpression/knockdown experiments, organoid models, clinical sample validation\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics plus functional rescue experiments in multiple models establishing the ALKBH5-IGF2BP2-CLSPN mRNA stability axis, single lab\",\n      \"pmids\": [\"41069850\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Claspin (CLSPN) functions as a DNA replication stress sensor that activates CHK1 (with loss-of-function variants reducing CHK1 phosphorylation), and its expression is post-transcriptionally regulated by m6A methylation via the ALKBH5/IGF2BP2 axis that controls CLSPN mRNA stability; additionally, Claspin overexpression can activate Wnt/β-catenin signaling to promote glycolysis and cell proliferation, though the biochemical mechanism linking Claspin to Wnt signaling remains unresolved.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Claspin (CLSPN) functions in the DNA replication stress response, where it is required for activation of the checkpoint kinase CHK1: a coding variant that causes partial exon skipping and reduced Claspin expression correspondingly diminishes CHK1 activation [#0]. Beyond this checkpoint role, CLSPN expression is controlled post-transcriptionally through m6A regulation, whereby ALKBH5-mediated demethylation destabilizes CLSPN mRNA in an IGF2BP2-dependent manner, such that low ALKBH5 permits IGF2BP2-dependent stabilization of the transcript and drives docetaxel resistance in prostate cancer [#3]. In oral squamous cell carcinoma, CLSPN overexpression promotes glycolysis and proliferation through activation of Wnt/\\u03b2-catenin signaling, with Wnt3a knockdown reversing these effects [#2], although the biochemical link between Claspin and Wnt signaling is not resolved in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that Claspin abundance is rate-limiting for CHK1 checkpoint activation by showing a splice-affecting coding variant reduces both Claspin expression and CHK1 phosphorylation.\",\n      \"evidence\": \"Minigene splicing assay and signaling/western blot experiments for the c.1574A>G (p.Asn525Ser) variant\",\n      \"pmids\": [\n        \"32847043\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not define the biochemical mechanism by which Claspin activates CHK1\",\n        \"Single study; effect of variant on patient phenotype not established\",\n        \"No structural characterization of the variant residue\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a promoter variant that elevates CLSPN transcription, indicating transcriptional regulation of Claspin levels.\",\n      \"evidence\": \"Luciferase reporter assay for the c.-68C>T promoter variant\",\n      \"pmids\": [\n        \"32847043\"\n      ],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single method (luciferase) without functional follow-up\",\n        \"Transcription factor responsible not identified\",\n        \"No link to downstream CHK1 or phenotype\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed CLSPN upstream of Wnt/\\u03b2-catenin signaling in cancer metabolism by showing its overexpression drives glycolysis and proliferation in a Wnt3a-dependent manner.\",\n      \"evidence\": \"Overexpression/knockdown, ECAR/OCR metabolic assays, xenografts, and Wnt3a-knockdown rescue in oral squamous cell carcinoma\",\n      \"pmids\": [\n        \"38237848\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Biochemical mechanism connecting Claspin to Wnt/\\u03b2-catenin not resolved\",\n        \"Relationship to Claspin's canonical checkpoint role unclear\",\n        \"No direct physical partner in the Wnt pathway identified\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined post-transcriptional control of CLSPN through an m6A axis, explaining how its mRNA stability is tuned and links it to chemotherapy resistance.\",\n      \"evidence\": \"Multi-omics, knockdown/overexpression, organoid models, and clinical samples establishing the ALKBH5\\u2013IGF2BP2\\u2013CLSPN mRNA stability axis in prostate cancer\",\n      \"pmids\": [\n        \"41069850\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"m6A site(s) on CLSPN mRNA not mapped\",\n        \"Single lab; mechanism of IGF2BP2-dependent stabilization not biochemically dissected\",\n        \"Connection between altered CLSPN levels and the checkpoint/Wnt functions not integrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism by which Claspin engages CHK1 and Wnt/\\u03b2-catenin signaling, and how its post-transcriptional regulation integrates with these functions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural or domain-level mechanism for CHK1 activation in the corpus\",\n        \"Direct molecular link between Claspin and Wnt/\\u03b2-catenin unknown\",\n        \"No reported direct physical interactors of Claspin in the timeline\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-8953897\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"loss","faith_supported":3,"faith_total":3,"faith_pct":100.0}}