{"gene":"TTC28","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2018,"finding":"Atypical cadherin Dchs1b interacts via a conserved motif in its intracellular domain with the tetratricopeptide (TTP) motifs of Ttc28, and regulates Ttc28 subcellular distribution; excess Ttc28 impairs embryonic cleavages and decreases microtubule turnover, while ttc28 inactivation increases microtubule turnover; genetic epistasis shows that ttc28 deficiency in dchs1b mutants suppresses cleavage furrow progression defects and midzone microtubule assembly defects.","method":"Co-immunoprecipitation/pulldown (Dchs1b–Ttc28 interaction), maternal-zygotic zebrafish mutant analysis, ttc28 inactivation and overexpression, Aurora B inhibitor sensitivity assays, genetic epistasis (double mutant rescue)","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assay, loss-of-function and gain-of-function experiments, and genetic epistasis in multiple orthogonal approaches within one study","pmids":["29738714"],"is_preprint":false},{"year":2024,"finding":"TTC28 protein interacts directly with HSPA8 (Hsc70) via its tetratricopeptide repeat domains binding the C-terminal PTIEEVD motif of HSPA8, and also interacts with LAMP2A; as a result, TTC28 is degraded via chaperone-mediated autophagy (CMA) and microautophagy. TTC28 knockout in human cancer cells triples the baseline frequency of micronuclei (7.7% vs. 2.3%), and TTC28 overexpression rescues this phenotype; TTC28 regulates mitosis and cytokinesis to maintain chromosomal stability, and CMA maintains chromosomal stability in a TTC28-dependent manner.","method":"Co-immunoprecipitation (TTC28–HSPA8, TTC28–LAMP2A), TTC28 knockout and overexpression in cancer cells, micronuclei frequency quantification, γH2AX assay, comet assay, bioinformatics (TCGA)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP defining binding partners with domain-level resolution, combined with KO/OE functional phenotype (micronuclei, γH2AX, comet), multiple orthogonal readouts in a single rigorous study","pmids":["39630868"],"is_preprint":false},{"year":2025,"finding":"CMA-mediated degradation via the TTC28–HSPA8 axis is confirmed as a master regulator of TTC28 protein levels and chromosomal stability; TTC28 downregulation by CMA contributes to chromosomal instability in cancer cells through effects on mitosis and cytokinesis.","method":"Serial functional experiments and bioinformatics analyses (follow-up/commentary on PMID:39630868)","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab follow-up commentary confirming mechanism from prior study; adds conceptual confirmation but no new orthogonal experiments described in abstract","pmids":["39893561"],"is_preprint":false},{"year":2014,"finding":"TTC28 harbors an active LINE-1 (L1) retrotransposon element that undergoes frequent somatic retrotransposition events in colorectal cancer, mobilizing neighboring DNA sequences (3' transductions) to other genomic loci including NOVA1; a germline retrotransposition from TTC28 to GABRA4 was identified as a common polymorphism in the Finnish population.","method":"Deep-coverage whole-genome sequencing of 92 CRC tumor-normal pairs, PCR validation of insertion events","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — WGS with PCR validation across 92 tumor-normal pairs; establishes TTC28 as a source locus for L1-mediated transductions","pmids":["24553397"],"is_preprint":false},{"year":2017,"finding":"TTC28-L1 mediated 3' transductions were identified in 34% of endometrioid ovarian carcinomas and 31% of clear cell ovarian carcinomas; transduction events were found to be clonal (present in ≥3 of 5 tumor samplings in 71% of cases), indicating that L1 activation from the TTC28 locus occurred early in EAOC development.","method":"Whole genome sequencing, PCR and capillary sequencing validation across multiple anatomical tumor sites","journal":"Gynecologic oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — WGS with PCR/Sanger validation across multiple tumor sites in independent EAOC cohort, replicating the TTC28 L1-source finding from PMID:24553397","pmids":["29032825"],"is_preprint":false},{"year":2025,"finding":"In zebrafish, loss of ttc28 suppresses epiboly progression defects caused by dchs1b deficiency, including defects in yolk cell microtubule dynamics (bundling and polymerization rate); Dchs1b-GFP fusion protein localizes to both cell membrane and cytoplasm during gastrulation; these findings extend the Dchs1b–Ttc28 regulatory axis from cleavage stages to epiboly.","method":"Genetic epistasis (dchs1b/ttc28 double mutants), homologous recombination knock-in of Dchs1b-GFP fusion, live imaging of microtubule dynamics, transcriptomic analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — preprint; genetic epistasis and live imaging are rigorous methods but single-lab and not yet peer-reviewed; extends prior peer-reviewed finding (PMID:29738714)","pmids":["40463075"],"is_preprint":true}],"current_model":"TTC28 is a large tetratricopeptide repeat (TPC) domain-containing protein that (1) binds to the intracellular domain of atypical cadherin Dchs1b via its TPR motifs and to Aurora B, thereby regulating microtubule dynamics and embryonic cleavage/epiboly in zebrafish; (2) interacts with HSPA8 (Hsc70) and LAMP2A, making it a substrate of chaperone-mediated autophagy (CMA), whose degradation controls chromosomal stability by regulating mitosis and cytokinesis; and (3) harbors an active LINE-1 retrotransposon that frequently undergoes somatic 3' transduction events in colorectal and gynecological cancers."},"narrative":{"mechanistic_narrative":"TTC28 is a tetratricopeptide repeat (TPR) protein that regulates microtubule dynamics during cell division and thereby safeguards chromosomal stability [PMID:29738714, PMID:39630868]. Through its TPR motifs, TTC28 binds the intracellular domain of the atypical cadherin Dchs1b, an interaction that controls its subcellular distribution; in zebrafish, excess Ttc28 impairs embryonic cleavage and reduces microtubule turnover, while loss of ttc28 increases turnover and suppresses the cleavage furrow and midzone microtubule defects of dchs1b mutants, placing TTC28 within an Aurora B–sensitive pathway governing cytokinesis [PMID:29738714]. In human cancer cells, TTC28 levels are set by chaperone-mediated and microautophagy: its TPR domains bind the C-terminal PTIEEVD motif of HSPA8 (Hsc70) and it engages LAMP2A, routing the protein for degradation; TTC28 loss triples micronucleus frequency and elevates DNA damage markers, while re-expression rescues this, establishing TTC28 as a regulator of mitosis and cytokinesis whose autophagic turnover modulates chromosomal instability [PMID:39630868]. Independently of its protein function, the TTC28 genomic locus harbors an active LINE-1 retrotransposon that undergoes frequent somatic 3' transduction events in colorectal and ovarian cancers [PMID:24553397, PMID:29032825].","teleology":[{"year":2014,"claim":"Before this work it was unclear which genomic loci act as active LINE-1 source elements in human tumors; this study established the TTC28 locus as a recurrent source of somatic L1-mediated 3' transductions, defining a cancer-relevant genomic property of the gene independent of its protein function.","evidence":"Deep whole-genome sequencing of 92 colorectal tumor-normal pairs with PCR validation of insertion events","pmids":["24553397"],"confidence":"Medium","gaps":["Does not address the function of the TTC28 protein","Mechanism linking L1 activation at this locus to tumorigenesis not established"]},{"year":2017,"claim":"It was unknown whether TTC28-L1 transposition was confined to colorectal cancer or occurred early in tumor evolution; clonal transduction events across multiple tumor samplings showed TTC28 L1 activation occurs early in ovarian carcinoma development and extends beyond colorectal cancer.","evidence":"Whole genome sequencing with PCR and capillary sequencing validation across multiple anatomical tumor sites in endometrioid and clear cell ovarian carcinomas","pmids":["29032825"],"confidence":"Medium","gaps":["Functional consequence of transduction events on tumor biology not determined","No link to the TTC28 protein's role"]},{"year":2018,"claim":"The molecular function of the TTC28 protein was uncharacterized; this work showed Ttc28 binds the atypical cadherin Dchs1b via its TPR motifs and regulates microtubule turnover, cleavage, and midzone microtubule assembly, defining a Dchs1b–Ttc28 axis controlling cell division.","evidence":"Co-IP/pulldown, maternal-zygotic zebrafish mutants, gain- and loss-of-function, Aurora B inhibitor sensitivity, and genetic epistasis (double-mutant rescue)","pmids":["29738714"],"confidence":"High","gaps":["Direct biochemical link between Ttc28 and microtubules not resolved","Relationship to Aurora B is inferred from inhibitor sensitivity, not direct binding","Human/mammalian relevance not tested in this study"]},{"year":2024,"claim":"How TTC28 levels are controlled and whether it functions in chromosomal stability in human cells was unknown; this study showed TTC28 binds HSPA8 (via the PTIEEVD motif) and LAMP2A and is degraded by chaperone-mediated autophagy, with TTC28 loss tripling micronucleus frequency, establishing it as an autophagy-regulated guardian of chromosomal stability acting through mitosis and cytokinesis.","evidence":"Reciprocal Co-IP defining domain-level binding, TTC28 knockout and rescue in cancer cells, micronuclei quantification, γH2AX and comet assays, TCGA analysis","pmids":["39630868"],"confidence":"High","gaps":["Direct substrate or molecular effector of TTC28 in mitosis not identified","How TTC28 mechanistically influences cytokinesis at the molecular level unresolved","Structural basis of TPR–PTIEEVD binding not determined"]},{"year":2025,"claim":"This follow-up reinforced that CMA-mediated degradation through the TTC28–HSPA8 axis is the master regulator of TTC28 levels and that its downregulation drives chromosomal instability in cancer.","evidence":"Serial functional experiments and bioinformatics (follow-up/commentary on the 2024 study)","pmids":["39893561"],"confidence":"Medium","gaps":["Single-lab follow-up adding conceptual confirmation rather than new orthogonal evidence","Does not resolve the downstream molecular target of TTC28"]},{"year":2025,"claim":"Whether the Dchs1b–Ttc28 axis acts beyond cleavage stages was unknown; loss of ttc28 was shown to suppress epiboly and yolk-cell microtubule dynamics defects of dchs1b mutants, extending the regulatory axis into gastrulation.","evidence":"Genetic epistasis (dchs1b/ttc28 double mutants), Dchs1b-GFP knock-in, live microtubule imaging, transcriptomics (preprint)","pmids":["40463075"],"confidence":"Medium","gaps":["Preprint, single-lab and not peer-reviewed","Direct effect of Ttc28 on microtubule polymerization not biochemically demonstrated"]},{"year":null,"claim":"The direct molecular effector through which TTC28 modulates microtubule dynamics and cytokinesis, and whether its developmental function in zebrafish and its CMA-regulated tumor-suppressive role in human cells reflect one unified mechanism, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified direct microtubule-binding or regulatory substrate","No structural model of TTC28","Integration of developmental and oncogenic/genome-stability roles not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":["DCHS1","HSPA8","LAMP2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96AY4","full_name":"Tetratricopeptide repeat protein 28","aliases":["TPR repeat-containing big gene cloned at Keio"],"length_aa":2481,"mass_kda":270.9,"function":"During mitosis, may be involved in the condensation of spindle midzone microtubules, leading to the formation of midbody","subcellular_location":"Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle; Cytoplasm, cytoskeleton, spindle pole; Midbody","url":"https://www.uniprot.org/uniprotkb/Q96AY4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TTC28","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NCKAP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TTC28","total_profiled":1310},"omim":[{"mim_id":"615098","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 28; TTC28","url":"https://www.omim.org/entry/615098"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Cytokinetic bridge","reliability":"Approved"},{"location":"Mitotic spindle","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TTC28"},"hgnc":{"alias_symbol":["KIAA1043"],"prev_symbol":[]},"alphafold":{"accession":"Q96AY4","domains":[{"cath_id":"1.25.40.10","chopping":"56-286","consensus_level":"medium","plddt":87.3817,"start":56,"end":286},{"cath_id":"-","chopping":"1197-1210_1217-1268_1417-1464","consensus_level":"medium","plddt":75.7861,"start":1197,"end":1464},{"cath_id":"1.20.58.2190","chopping":"1720-1827","consensus_level":"medium","plddt":79.9606,"start":1720,"end":1827},{"cath_id":"1.20.58","chopping":"1834-1869_1880-1943","consensus_level":"medium","plddt":75.801,"start":1834,"end":1943}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96AY4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96AY4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96AY4-F1-predicted_aligned_error_v6.png","plddt_mean":68.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TTC28","jax_strain_url":"https://www.jax.org/strain/search?query=TTC28"},"sequence":{"accession":"Q96AY4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96AY4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96AY4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96AY4"}},"corpus_meta":[{"pmid":"28548104","id":"PMC_28548104","title":"Genomic 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a conserved motif in its intracellular domain with the tetratricopeptide (TTP) motifs of Ttc28, and regulates Ttc28 subcellular distribution; excess Ttc28 impairs embryonic cleavages and decreases microtubule turnover, while ttc28 inactivation increases microtubule turnover; genetic epistasis shows that ttc28 deficiency in dchs1b mutants suppresses cleavage furrow progression defects and midzone microtubule assembly defects.\",\n      \"method\": \"Co-immunoprecipitation/pulldown (Dchs1b–Ttc28 interaction), maternal-zygotic zebrafish mutant analysis, ttc28 inactivation and overexpression, Aurora B inhibitor sensitivity assays, genetic epistasis (double mutant rescue)\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assay, loss-of-function and gain-of-function experiments, and genetic epistasis in multiple orthogonal approaches within one study\",\n      \"pmids\": [\"29738714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TTC28 protein interacts directly with HSPA8 (Hsc70) via its tetratricopeptide repeat domains binding the C-terminal PTIEEVD motif of HSPA8, and also interacts with LAMP2A; as a result, TTC28 is degraded via chaperone-mediated autophagy (CMA) and microautophagy. TTC28 knockout in human cancer cells triples the baseline frequency of micronuclei (7.7% vs. 2.3%), and TTC28 overexpression rescues this phenotype; TTC28 regulates mitosis and cytokinesis to maintain chromosomal stability, and CMA maintains chromosomal stability in a TTC28-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation (TTC28–HSPA8, TTC28–LAMP2A), TTC28 knockout and overexpression in cancer cells, micronuclei frequency quantification, γH2AX assay, comet assay, bioinformatics (TCGA)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP defining binding partners with domain-level resolution, combined with KO/OE functional phenotype (micronuclei, γH2AX, comet), multiple orthogonal readouts in a single rigorous study\",\n      \"pmids\": [\"39630868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CMA-mediated degradation via the TTC28–HSPA8 axis is confirmed as a master regulator of TTC28 protein levels and chromosomal stability; TTC28 downregulation by CMA contributes to chromosomal instability in cancer cells through effects on mitosis and cytokinesis.\",\n      \"method\": \"Serial functional experiments and bioinformatics analyses (follow-up/commentary on PMID:39630868)\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab follow-up commentary confirming mechanism from prior study; adds conceptual confirmation but no new orthogonal experiments described in abstract\",\n      \"pmids\": [\"39893561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TTC28 harbors an active LINE-1 (L1) retrotransposon element that undergoes frequent somatic retrotransposition events in colorectal cancer, mobilizing neighboring DNA sequences (3' transductions) to other genomic loci including NOVA1; a germline retrotransposition from TTC28 to GABRA4 was identified as a common polymorphism in the Finnish population.\",\n      \"method\": \"Deep-coverage whole-genome sequencing of 92 CRC tumor-normal pairs, PCR validation of insertion events\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — WGS with PCR validation across 92 tumor-normal pairs; establishes TTC28 as a source locus for L1-mediated transductions\",\n      \"pmids\": [\"24553397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TTC28-L1 mediated 3' transductions were identified in 34% of endometrioid ovarian carcinomas and 31% of clear cell ovarian carcinomas; transduction events were found to be clonal (present in ≥3 of 5 tumor samplings in 71% of cases), indicating that L1 activation from the TTC28 locus occurred early in EAOC development.\",\n      \"method\": \"Whole genome sequencing, PCR and capillary sequencing validation across multiple anatomical tumor sites\",\n      \"journal\": \"Gynecologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — WGS with PCR/Sanger validation across multiple tumor sites in independent EAOC cohort, replicating the TTC28 L1-source finding from PMID:24553397\",\n      \"pmids\": [\"29032825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish, loss of ttc28 suppresses epiboly progression defects caused by dchs1b deficiency, including defects in yolk cell microtubule dynamics (bundling and polymerization rate); Dchs1b-GFP fusion protein localizes to both cell membrane and cytoplasm during gastrulation; these findings extend the Dchs1b–Ttc28 regulatory axis from cleavage stages to epiboly.\",\n      \"method\": \"Genetic epistasis (dchs1b/ttc28 double mutants), homologous recombination knock-in of Dchs1b-GFP fusion, live imaging of microtubule dynamics, transcriptomic analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint; genetic epistasis and live imaging are rigorous methods but single-lab and not yet peer-reviewed; extends prior peer-reviewed finding (PMID:29738714)\",\n      \"pmids\": [\"40463075\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TTC28 is a large tetratricopeptide repeat (TPC) domain-containing protein that (1) binds to the intracellular domain of atypical cadherin Dchs1b via its TPR motifs and to Aurora B, thereby regulating microtubule dynamics and embryonic cleavage/epiboly in zebrafish; (2) interacts with HSPA8 (Hsc70) and LAMP2A, making it a substrate of chaperone-mediated autophagy (CMA), whose degradation controls chromosomal stability by regulating mitosis and cytokinesis; and (3) harbors an active LINE-1 retrotransposon that frequently undergoes somatic 3' transduction events in colorectal and gynecological cancers.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TTC28 is a tetratricopeptide repeat (TPR) protein that regulates microtubule dynamics during cell division and thereby safeguards chromosomal stability [#0, #1]. Through its TPR motifs, TTC28 binds the intracellular domain of the atypical cadherin Dchs1b, an interaction that controls its subcellular distribution; in zebrafish, excess Ttc28 impairs embryonic cleavage and reduces microtubule turnover, while loss of ttc28 increases turnover and suppresses the cleavage furrow and midzone microtubule defects of dchs1b mutants, placing TTC28 within an Aurora B–sensitive pathway governing cytokinesis [#0]. In human cancer cells, TTC28 levels are set by chaperone-mediated and microautophagy: its TPR domains bind the C-terminal PTIEEVD motif of HSPA8 (Hsc70) and it engages LAMP2A, routing the protein for degradation; TTC28 loss triples micronucleus frequency and elevates DNA damage markers, while re-expression rescues this, establishing TTC28 as a regulator of mitosis and cytokinesis whose autophagic turnover modulates chromosomal instability [#1]. Independently of its protein function, the TTC28 genomic locus harbors an active LINE-1 retrotransposon that undergoes frequent somatic 3' transduction events in colorectal and ovarian cancers [#3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Before this work it was unclear which genomic loci act as active LINE-1 source elements in human tumors; this study established the TTC28 locus as a recurrent source of somatic L1-mediated 3' transductions, defining a cancer-relevant genomic property of the gene independent of its protein function.\",\n      \"evidence\": \"Deep whole-genome sequencing of 92 colorectal tumor-normal pairs with PCR validation of insertion events\",\n      \"pmids\": [\"24553397\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Does not address the function of the TTC28 protein\", \"Mechanism linking L1 activation at this locus to tumorigenesis not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"It was unknown whether TTC28-L1 transposition was confined to colorectal cancer or occurred early in tumor evolution; clonal transduction events across multiple tumor samplings showed TTC28 L1 activation occurs early in ovarian carcinoma development and extends beyond colorectal cancer.\",\n      \"evidence\": \"Whole genome sequencing with PCR and capillary sequencing validation across multiple anatomical tumor sites in endometrioid and clear cell ovarian carcinomas\",\n      \"pmids\": [\"29032825\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional consequence of transduction events on tumor biology not determined\", \"No link to the TTC28 protein's role\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The molecular function of the TTC28 protein was uncharacterized; this work showed Ttc28 binds the atypical cadherin Dchs1b via its TPR motifs and regulates microtubule turnover, cleavage, and midzone microtubule assembly, defining a Dchs1b–Ttc28 axis controlling cell division.\",\n      \"evidence\": \"Co-IP/pulldown, maternal-zygotic zebrafish mutants, gain- and loss-of-function, Aurora B inhibitor sensitivity, and genetic epistasis (double-mutant rescue)\",\n      \"pmids\": [\"29738714\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct biochemical link between Ttc28 and microtubules not resolved\", \"Relationship to Aurora B is inferred from inhibitor sensitivity, not direct binding\", \"Human/mammalian relevance not tested in this study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"How TTC28 levels are controlled and whether it functions in chromosomal stability in human cells was unknown; this study showed TTC28 binds HSPA8 (via the PTIEEVD motif) and LAMP2A and is degraded by chaperone-mediated autophagy, with TTC28 loss tripling micronucleus frequency, establishing it as an autophagy-regulated guardian of chromosomal stability acting through mitosis and cytokinesis.\",\n      \"evidence\": \"Reciprocal Co-IP defining domain-level binding, TTC28 knockout and rescue in cancer cells, micronuclei quantification, \\u03b3H2AX and comet assays, TCGA analysis\",\n      \"pmids\": [\"39630868\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct substrate or molecular effector of TTC28 in mitosis not identified\", \"How TTC28 mechanistically influences cytokinesis at the molecular level unresolved\", \"Structural basis of TPR–PTIEEVD binding not determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"This follow-up reinforced that CMA-mediated degradation through the TTC28–HSPA8 axis is the master regulator of TTC28 levels and that its downregulation drives chromosomal instability in cancer.\",\n      \"evidence\": \"Serial functional experiments and bioinformatics (follow-up/commentary on the 2024 study)\",\n      \"pmids\": [\"39893561\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single-lab follow-up adding conceptual confirmation rather than new orthogonal evidence\", \"Does not resolve the downstream molecular target of TTC28\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether the Dchs1b–Ttc28 axis acts beyond cleavage stages was unknown; loss of ttc28 was shown to suppress epiboly and yolk-cell microtubule dynamics defects of dchs1b mutants, extending the regulatory axis into gastrulation.\",\n      \"evidence\": \"Genetic epistasis (dchs1b/ttc28 double mutants), Dchs1b-GFP knock-in, live microtubule imaging, transcriptomics (preprint)\",\n      \"pmids\": [\"40463075\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Preprint, single-lab and not peer-reviewed\", \"Direct effect of Ttc28 on microtubule polymerization not biochemically demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular effector through which TTC28 modulates microtubule dynamics and cytokinesis, and whether its developmental function in zebrafish and its CMA-regulated tumor-suppressive role in human cells reflect one unified mechanism, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No identified direct microtubule-binding or regulatory substrate\", \"No structural model of TTC28\", \"Integration of developmental and oncogenic/genome-stability roles not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DCHS1\", \"HSPA8\", \"LAMP2A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}