{"gene":"CETN2","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2001,"finding":"Mouse centrin 2 (CETN2) protein localizes to the region immediately surrounding the centrioles in the centrosome of NIH 3T3 cells, as demonstrated by immunofluorescence microscopy. CETN2 encodes a 172 amino acid EF-hand calcium-binding protein and is ubiquitously expressed in adult mouse tissues.","method":"Immunofluorescence microscopy, Northern blot, RT-PCR, FISH","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence with multiple supporting methods (FISH, Northern blot, RT-PCR) in a single lab","pmids":["11250075"],"is_preprint":false},{"year":2019,"finding":"CETN2 and CETN3 cooperate to stabilize the photoreceptor connecting cilium (CC) axoneme structure; simultaneous deletion of both Cetn2 and Cetn3 in mice destabilizes the photoreceptor axoneme, reduces CC length, depletes SPATA7 from the distal CC, and causes radial expansion of the axoneme with misaligned outer segment discs, ultimately leading to retinal degeneration — whereas single knockouts of either gene alone do not affect photoreceptor function.","method":"Double-knockout mouse model (Cetn2-/-;Cetn3GT/GT), electroretinography (ERG), immunofluorescence, ultrastructural analysis (electron microscopy)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic double-knockout with multiple orthogonal readouts (ERG, immunofluorescence, EM ultrastructure), including epistasis via single vs. double KO comparison","pmids":["30647131"],"is_preprint":false},{"year":2025,"finding":"CETN2 forms a complex with XPC (a key initiator of nucleotide excision repair, NER), enhancing NER activity and thereby reducing the cytotoxic efficacy of oxaliplatin in hepatocellular carcinoma (HCC) cells. siRNA-mediated knockdown of CETN2 increased oxaliplatin-induced cytotoxicity and apoptosis, while CETN2 overexpression inhibited oxaliplatin-induced DNA damage in a manner partially reversed by XPC knockdown.","method":"Co-immunoprecipitation (complex formation with XPC), siRNA knockdown, overexpression, cytotoxicity and apoptosis assays, DNA damage assays in HCC cell lines","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complex formation with XPC supported by functional rescue (XPC knockdown partially reverses CETN2 overexpression effect), multiple orthogonal methods in a single lab","pmids":["39945187"],"is_preprint":false}],"current_model":"CETN2 is an EF-hand calcium-binding protein that localizes to the centrosome/centriole region, cooperates with CETN3 to stabilize the photoreceptor connecting cilium axoneme, and participates in nucleotide excision repair (NER) by forming a complex with XPC to facilitate initial DNA damage recognition, thereby modulating cellular sensitivity to platinum-based chemotherapy."},"narrative":{"mechanistic_narrative":"CETN2 is a ubiquitously expressed EF-hand calcium-binding protein that operates at the centriole/centrosome and within DNA damage recognition machinery [PMID:11250075]. At ciliary structures, CETN2 acts redundantly with CETN3 to stabilize the photoreceptor connecting cilium axoneme: combined loss of both centrins, but neither alone, destabilizes the axoneme, shortens the connecting cilium, depletes SPATA7 from its distal region, misaligns outer segment discs, and drives retinal degeneration [PMID:30647131]. In a distinct functional context, CETN2 forms a complex with the nucleotide excision repair initiator XPC, enhancing NER activity; this complex limits oxaliplatin-induced DNA damage and cytotoxicity, such that CETN2 depletion sensitizes hepatocellular carcinoma cells to oxaliplatin in an XPC-dependent manner [PMID:39945187]. Beyond these centriolar, ciliary, and NER roles, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2001,"claim":"Established the basic identity and subcellular address of CETN2, defining it as a calcium-binding protein concentrated at the centriolar region rather than diffusely distributed.","evidence":"Immunofluorescence microscopy, Northern blot, RT-PCR and FISH for mouse CETN2 in NIH 3T3 cells and adult tissues","pmids":["11250075"],"confidence":"Medium","gaps":["Calcium-dependent conformational or binding behavior not functionally tested","No interacting partners identified","Cellular consequence of CETN2 loss not addressed"]},{"year":2019,"claim":"Resolved why single centrin loss is phenotypically silent by showing CETN2 and CETN3 act redundantly to maintain photoreceptor connecting cilium architecture, linking centrin function to ciliary stability and retinal integrity.","evidence":"Cetn2/Cetn3 double-knockout mice analyzed by ERG, immunofluorescence, and electron microscopy ultrastructure","pmids":["30647131"],"confidence":"High","gaps":["Molecular mechanism by which centrins stabilize the axoneme is undefined","Direct relationship between CETN2 and SPATA7 retention not established","Calcium dependence of the ciliary role not tested"]},{"year":2025,"claim":"Connected CETN2 to DNA repair by showing it complexes with XPC to promote NER, framing CETN2 as a determinant of chemotherapy response.","evidence":"Co-immunoprecipitation, siRNA knockdown, overexpression, and DNA damage/apoptosis assays with oxaliplatin in HCC cell lines, with XPC-knockdown rescue","pmids":["39945187"],"confidence":"Medium","gaps":["Single-lab Co-IP without reciprocal validation or structural mapping of the CETN2-XPC interface","Step in NER that CETN2 facilitates is not pinpointed","Whether the centriolar pool and the NER pool of CETN2 are functionally distinct is unknown"]},{"year":null,"claim":"How CETN2's calcium-binding activity mechanistically couples its centriolar/ciliary structural role to its NER function remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CETN2 in either context","Calcium-dependence of any documented function untested","Integration of ciliary and DNA-repair roles unexplained"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2]}],"complexes":[],"partners":["XPC","CETN3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P41208","full_name":"Centrin-2","aliases":["Caltractin isoform 1"],"length_aa":172,"mass_kda":19.7,"function":"Plays a fundamental role in microtubule organizing center structure and function. Required for centriole duplication and correct spindle formation. Has a role in regulating cytokinesis and genome stability via cooperation with CALM1 and CCP110 Involved in global genome nucleotide excision repair (GG-NER) by acting as component of the XPC complex. Cooperatively with RAD23B appears to stabilize XPC. In vitro, stimulates DNA binding of the XPC:RAD23B dimer The XPC complex is proposed to represent the first factor bound at the sites of DNA damage and together with other core recognition factors, XPA, RPA and the TFIIH complex, is part of the pre-incision (or initial recognition) complex. The XPC complex recognizes a wide spectrum of damaged DNA characterized by distortions of the DNA helix such as single-stranded loops, mismatched bubbles or single-stranded overhangs. The orientation of XPC complex binding appears to be crucial for inducing a productive NER. XPC complex is proposed to recognize and to interact with unpaired bases on the undamaged DNA strand which is followed by recruitment of the TFIIH complex and subsequent scanning for lesions in the opposite strand in a 5'-to-3' direction by the NER machinery. Cyclobutane pyrimidine dimers (CPDs) which are formed upon UV-induced DNA damage esacpe detection by the XPC complex due to a low degree of structural perurbation. Instead they are detected by the UV-DDB complex which in turn recruits and cooperates with the XPC complex in the respective DNA repair As a component of the TREX-2 complex, involved in the export of mRNAs to the cytoplasm through the nuclear pores","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Nucleus envelope; Nucleus, nuclear pore complex; Nucleus","url":"https://www.uniprot.org/uniprotkb/P41208/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CETN2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000147400","cell_line_id":"CID000205","localizations":[{"compartment":"centrosome","grade":3},{"compartment":"chromatin","grade":2},{"compartment":"cytoplasmic","grade":2},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"CETN3","stoichiometry":10.0},{"gene":"RAD23B","stoichiometry":10.0},{"gene":"XPC","stoichiometry":4.0},{"gene":"PKN2","stoichiometry":4.0},{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CDC7","stoichiometry":0.2},{"gene":"CDK7","stoichiometry":0.2},{"gene":"GTF2H5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000205","total_profiled":1310},"omim":[{"mim_id":"617880","title":"POC5 CENTRIOLAR PROTEIN; POC5","url":"https://www.omim.org/entry/617880"},{"mim_id":"613037","title":"INOSITOL POLYPHOSPHATE-5-PHOSPHATASE, 72-KD; INPP5E","url":"https://www.omim.org/entry/613037"},{"mim_id":"612765","title":"SFI1 CENTRIN-BINDING PROTEIN; SFI1","url":"https://www.omim.org/entry/612765"},{"mim_id":"611425","title":"CENTROBIN, CENTRIOLE DUPLICATION AND SPINDLE ASSEMBLY PROTEIN; CNTROB","url":"https://www.omim.org/entry/611425"},{"mim_id":"609321","title":"SAS6 CENTRIOLAR ASSEMBLY PROTEIN; SASS6","url":"https://www.omim.org/entry/609321"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Flagellar centriole","reliability":"Supported"},{"location":"Centrosome","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"choroid plexus","ntpm":233.9},{"tissue":"fallopian tube","ntpm":229.2}],"url":"https://www.proteinatlas.org/search/CETN2"},"hgnc":{"alias_symbol":["CEN2"],"prev_symbol":["CALT"]},"alphafold":{"accession":"P41208","domains":[{"cath_id":"1.10.238.10","chopping":"26-100","consensus_level":"high","plddt":91.3912,"start":26,"end":100},{"cath_id":"1.10.238.10","chopping":"114-168","consensus_level":"high","plddt":94.8735,"start":114,"end":168}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P41208","model_url":"https://alphafold.ebi.ac.uk/files/AF-P41208-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P41208-F1-predicted_aligned_error_v6.png","plddt_mean":85.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CETN2","jax_strain_url":"https://www.jax.org/strain/search?query=CETN2"},"sequence":{"accession":"P41208","fasta_url":"https://rest.uniprot.org/uniprotkb/P41208.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P41208/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P41208"}},"corpus_meta":[{"pmid":"22442734","id":"PMC_22442734","title":"Conjunctiva-associated lymphoid tissue (CALT) reactions to antiglaucoma prostaglandins with or without BAK-preservative in rabbit acute toxicity study.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22442734","citation_count":32,"is_preprint":false},{"pmid":"8091860","id":"PMC_8091860","title":"Sequence around the centromere of Saccharomyces cerevisiae chromosome II: similarity of CEN2 to CEN4.","date":"1994","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/8091860","citation_count":25,"is_preprint":false},{"pmid":"30647131","id":"PMC_30647131","title":"Deletion of both centrin 2 (CETN2) and CETN3 destabilizes the distal connecting cilium of mouse photoreceptors.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30647131","citation_count":22,"is_preprint":false},{"pmid":"22823013","id":"PMC_22823013","title":"Conjunctival instillation of retinal antigens induces tolerance Does it invoke mucosal tolerance mediated via conjunctiva associated lymphoid tissues (CALT)?","date":"1994","source":"Ocular immunology and inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/22823013","citation_count":21,"is_preprint":false},{"pmid":"11250075","id":"PMC_11250075","title":"Characterization of the X-linked murine centrin Cetn2 gene.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11250075","citation_count":19,"is_preprint":false},{"pmid":"33053795","id":"PMC_33053795","title":"Disease-Specific Expression of Conjunctiva Associated Lymphoid Tissue (CALT) in Mouse Models of Dry Eye Disease and Ocular Allergy.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33053795","citation_count":16,"is_preprint":false},{"pmid":"8944092","id":"PMC_8944092","title":"The effect of topical cyclosporin on conjunctiva-associated lymphoid tissue (CALT).","date":"1996","source":"Eye (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/8944092","citation_count":14,"is_preprint":false},{"pmid":"27560164","id":"PMC_27560164","title":"Novel Centromeric Loci of the Wine and Beer Yeast Dekkera bruxellensis CEN1 and CEN2.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27560164","citation_count":11,"is_preprint":false},{"pmid":"21923825","id":"PMC_21923825","title":"Characterization of membranous (M) cells in normal feline conjunctiva-associated lymphoid tissue (CALT).","date":"2011","source":"Veterinary ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/21923825","citation_count":7,"is_preprint":false},{"pmid":"39945187","id":"PMC_39945187","title":"Role of the nucleotide excision repair function of CETN2 in the inhibition of the sensitivity of hepatocellular carcinoma cells to oxaliplatin.","date":"2025","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/39945187","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7060,"output_tokens":914,"usd":0.017445,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7432,"output_tokens":1517,"usd":0.037542,"stage2_stop_reason":"end_turn"},"total_usd":0.054987,"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\": 2001,\n      \"finding\": \"Mouse centrin 2 (CETN2) protein localizes to the region immediately surrounding the centrioles in the centrosome of NIH 3T3 cells, as demonstrated by immunofluorescence microscopy. CETN2 encodes a 172 amino acid EF-hand calcium-binding protein and is ubiquitously expressed in adult mouse tissues.\",\n      \"method\": \"Immunofluorescence microscopy, Northern blot, RT-PCR, FISH\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence with multiple supporting methods (FISH, Northern blot, RT-PCR) in a single lab\",\n      \"pmids\": [\"11250075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CETN2 and CETN3 cooperate to stabilize the photoreceptor connecting cilium (CC) axoneme structure; simultaneous deletion of both Cetn2 and Cetn3 in mice destabilizes the photoreceptor axoneme, reduces CC length, depletes SPATA7 from the distal CC, and causes radial expansion of the axoneme with misaligned outer segment discs, ultimately leading to retinal degeneration — whereas single knockouts of either gene alone do not affect photoreceptor function.\",\n      \"method\": \"Double-knockout mouse model (Cetn2-/-;Cetn3GT/GT), electroretinography (ERG), immunofluorescence, ultrastructural analysis (electron microscopy)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic double-knockout with multiple orthogonal readouts (ERG, immunofluorescence, EM ultrastructure), including epistasis via single vs. double KO comparison\",\n      \"pmids\": [\"30647131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CETN2 forms a complex with XPC (a key initiator of nucleotide excision repair, NER), enhancing NER activity and thereby reducing the cytotoxic efficacy of oxaliplatin in hepatocellular carcinoma (HCC) cells. siRNA-mediated knockdown of CETN2 increased oxaliplatin-induced cytotoxicity and apoptosis, while CETN2 overexpression inhibited oxaliplatin-induced DNA damage in a manner partially reversed by XPC knockdown.\",\n      \"method\": \"Co-immunoprecipitation (complex formation with XPC), siRNA knockdown, overexpression, cytotoxicity and apoptosis assays, DNA damage assays in HCC cell lines\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complex formation with XPC supported by functional rescue (XPC knockdown partially reverses CETN2 overexpression effect), multiple orthogonal methods in a single lab\",\n      \"pmids\": [\"39945187\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CETN2 is an EF-hand calcium-binding protein that localizes to the centrosome/centriole region, cooperates with CETN3 to stabilize the photoreceptor connecting cilium axoneme, and participates in nucleotide excision repair (NER) by forming a complex with XPC to facilitate initial DNA damage recognition, thereby modulating cellular sensitivity to platinum-based chemotherapy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CETN2 is a ubiquitously expressed EF-hand calcium-binding protein that operates at the centriole/centrosome and within DNA damage recognition machinery [#0]. At ciliary structures, CETN2 acts redundantly with CETN3 to stabilize the photoreceptor connecting cilium axoneme: combined loss of both centrins, but neither alone, destabilizes the axoneme, shortens the connecting cilium, depletes SPATA7 from its distal region, misaligns outer segment discs, and drives retinal degeneration [#1]. In a distinct functional context, CETN2 forms a complex with the nucleotide excision repair initiator XPC, enhancing NER activity; this complex limits oxaliplatin-induced DNA damage and cytotoxicity, such that CETN2 depletion sensitizes hepatocellular carcinoma cells to oxaliplatin in an XPC-dependent manner [#2]. Beyond these centriolar, ciliary, and NER roles, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the basic identity and subcellular address of CETN2, defining it as a calcium-binding protein concentrated at the centriolar region rather than diffusely distributed.\",\n      \"evidence\": \"Immunofluorescence microscopy, Northern blot, RT-PCR and FISH for mouse CETN2 in NIH 3T3 cells and adult tissues\",\n      \"pmids\": [\"11250075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Calcium-dependent conformational or binding behavior not functionally tested\", \"No interacting partners identified\", \"Cellular consequence of CETN2 loss not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved why single centrin loss is phenotypically silent by showing CETN2 and CETN3 act redundantly to maintain photoreceptor connecting cilium architecture, linking centrin function to ciliary stability and retinal integrity.\",\n      \"evidence\": \"Cetn2/Cetn3 double-knockout mice analyzed by ERG, immunofluorescence, and electron microscopy ultrastructure\",\n      \"pmids\": [\"30647131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which centrins stabilize the axoneme is undefined\", \"Direct relationship between CETN2 and SPATA7 retention not established\", \"Calcium dependence of the ciliary role not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected CETN2 to DNA repair by showing it complexes with XPC to promote NER, framing CETN2 as a determinant of chemotherapy response.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, and DNA damage/apoptosis assays with oxaliplatin in HCC cell lines, with XPC-knockdown rescue\",\n      \"pmids\": [\"39945187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP without reciprocal validation or structural mapping of the CETN2-XPC interface\", \"Step in NER that CETN2 facilitates is not pinpointed\", \"Whether the centriolar pool and the NER pool of CETN2 are functionally distinct is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CETN2's calcium-binding activity mechanistically couples its centriolar/ciliary structural role to its NER function remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CETN2 in either context\", \"Calcium-dependence of any documented function untested\", \"Integration of ciliary and DNA-repair roles unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"XPC\", \"CETN3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}