{"gene":"DOP1A","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2019,"finding":"Dopey1 and Mon2 assemble into a complex that localizes to the Golgi, endolysosome, and ER exit sites; Golgi localization of Dopey1 requires binding to phosphatidylinositol-4-phosphate (PI4P), while Mon2 localization requires phosphatidic acid (PA). The N-terminus of Dopey1 further interacts with kinesin-1, and the Dopey1-Mon2 complex functions as a dual-lipid-regulated cargo adaptor to recruit kinesin-1 to secretory and endocytic organelles for centrifugally biased bidirectional transport.","method":"Co-immunoprecipitation, lipid-binding assays, co-localization imaging, organelle fractionation, functional transport assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, lipid-binding assays, multiple orthogonal methods including localization and transport functional readouts in a single rigorous study","pmids":["31324769"],"is_preprint":false},{"year":2014,"finding":"A nonsense mutation in Dopey1 (rat ortholog of DOP1A) causes hypomyelination and periaxonal vacuole formation in the VF rat; DOPEY1 protein is expressed in neurons and oligodendrocytes, and its loss leads to accumulation of myelin components (proteolipid protein and myelin-associated glycoprotein) in the oligodendrocyte cell body, implicating Dopey1 in intracellular trafficking of myelin components.","method":"Genetic mapping, Sanger sequencing, immunohistochemistry, Western blot, mRNA expression analysis","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function rat model with defined cellular phenotype (myelin component accumulation), multiple methods but single lab","pmids":["24863653"],"is_preprint":false},{"year":2025,"finding":"H. pylori infection upregulates DOPEY1 expression via a CagA-dependent pathway; DOPEY1 interacts with USP7 and TRIP12, and this complex promotes p53 degradation. DOPEY1 silencing reverses p53 degradation, and USP7 overexpression rescues p53 degradation in DOPEY1-silenced cells, placing DOPEY1 upstream of the USP7/TRIP12 axis in p53 regulation.","method":"Liquid chromatography-mass spectrometry (interactome), co-immunoprecipitation, siRNA knockdown, overexpression rescue, mouse tumor model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP confirmed by LC-MS interactome, functional rescue experiment, in vivo tumor model; single lab","pmids":["39939725"],"is_preprint":false},{"year":2026,"finding":"Under mTOR signaling control, a shortage of lysophosphatidic acid (LPA) triggers rapid relocalization of Dop1a to nuclear pore complexes (NPCs), where Dop1a binds AGPAT2 and suppresses phospholipid (PL) synthesis. Loss of Dop1a leads to elevated PL production, nuclear lipid droplet formation, and nuclear accumulation of CDK2, impairing cell cycle entry; thus Dop1a safeguards cell division by regulating nuclear membrane PL homeostasis.","method":"Live-cell imaging/localization assay, co-immunoprecipitation (Dop1a-AGPAT2), knockout/loss-of-function with lipidomic and cell cycle readouts, mTOR inhibitor treatment","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments linked to functional consequence, Co-IP of binding partner, loss-of-function with multiple orthogonal readouts; single lab","pmids":["42164854"],"is_preprint":false},{"year":2025,"finding":"DOP1A protein is expressed in oligodendrocyte progenitor cells (OPCs) as well as mature oligodendrocytes in the rat CNS; DOP1A dysfunction (via nonsense mutation) causes impaired differentiation and maturation of oligodendrocyte-lineage cells and disrupted intracellular trafficking of myelin basic protein (Mbp) mRNAs in oligodendrocytes, resulting in hypomyelination.","method":"Immunolabeling (anti-APC/CC1, transcription factor markers), mRNA localization analysis, VF rat loss-of-function model","journal":"Veterinary Pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotype with multiple marker readouts in a genetic loss-of-function model; single lab, no in vitro mechanistic reconstitution","pmids":["41067867"],"is_preprint":false},{"year":2025,"finding":"Removal of a microexon in dop1a in zebrafish (using CRISPR/Cas9) produces mild neural phenotypes in larval brain activity, establishing that the microexon contributes to DOP1A function during neurodevelopment.","method":"CRISPR/Cas9 microexon deletion in zebrafish, larval brain activity imaging and behavioral assays","journal":"eLife","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (CRISPR KO), mild phenotype, no molecular mechanism defined for the microexon's contribution","pmids":["41252186"],"is_preprint":false}],"current_model":"DOP1A (DOPEY1) functions as a dual-lipid-regulated cargo adaptor: in complex with Mon2, it binds PI4P (via Dopey1) and phosphatidic acid (via Mon2) at Golgi and endocytic organelles, recruits kinesin-1 via its N-terminus to drive centrifugally biased vesicle transport, and is required for myelin component trafficking in oligodendrocytes; additionally, under mTOR signaling, DOP1A relocates to nuclear pore complexes where it binds AGPAT2 to suppress phospholipid synthesis and safeguard cell division, and in the context of H. pylori infection it interacts with USP7 and TRIP12 to promote p53 degradation."},"narrative":{"mechanistic_narrative":"DOP1A (DOPEY1) is a dual-lipid-regulated cargo adaptor that couples organelle membranes to microtubule-based transport: in complex with Mon2 it localizes to the Golgi, endolysosomes, and ER exit sites, where Dopey1 binds PI4P and Mon2 binds phosphatidic acid, and the Dopey1 N-terminus recruits kinesin-1 to drive centrifugally biased bidirectional vesicle transport [PMID:31324769]. This trafficking function is required in the nervous system, where loss-of-function causes mislocalization of myelin components — proteolipid protein and myelin-associated glycoprotein accumulate in the oligodendrocyte cell body and myelin basic protein mRNA fails to be properly trafficked — producing impaired oligodendrocyte differentiation and hypomyelination [PMID:24863653, PMID:41067867]. Beyond its trafficking role, DOP1A acts in lipid homeostasis at the nuclear envelope: under mTOR control, a shortage of lysophosphatidic acid relocalizes Dop1a to nuclear pore complexes where it binds AGPAT2 to suppress phospholipid synthesis, and its loss elevates phospholipid production, drives nuclear lipid droplet formation, and impairs cell cycle entry through nuclear CDK2 accumulation [PMID:42164854]. DOP1A is also co-opted during Helicobacter pylori infection, where CagA-dependent upregulation of DOPEY1 enables it to act with USP7 and TRIP12 to promote p53 degradation [PMID:39939725].","teleology":[{"year":2014,"claim":"Whether DOP1A has a defined cellular function was unknown; a rat loss-of-function model established its role in intracellular trafficking of myelin components in oligodendrocytes.","evidence":"Genetic mapping and nonsense mutation in the VF rat with immunohistochemistry and Western blot for myelin proteins","pmids":["24863653"],"confidence":"Medium","gaps":["No molecular mechanism for how DOPEY1 mediates myelin component trafficking","No identification of binding partners or cargo at this stage","Phenotype defined in rat ortholog only"]},{"year":2019,"claim":"The biochemical basis of DOP1A trafficking activity was undefined; this work established the Dopey1-Mon2 complex as a dual-lipid-regulated cargo adaptor that recruits kinesin-1 to secretory and endocytic organelles.","evidence":"Reciprocal Co-IP, lipid-binding assays, co-localization imaging, organelle fractionation, and functional transport assays","pmids":["31324769"],"confidence":"High","gaps":["Cargo identity for the kinesin-1-driven transport not defined","Link between this adaptor mechanism and the myelin trafficking phenotype not directly demonstrated","Structural basis of PI4P and PA recognition not resolved"]},{"year":2025,"claim":"Whether DOP1A is co-opted in disease was unknown; H. pylori work placed DOPEY1 upstream of a USP7/TRIP12 axis that degrades p53.","evidence":"LC-MS interactome, reciprocal Co-IP, siRNA knockdown, overexpression rescue, and mouse tumor model","pmids":["39939725"],"confidence":"Medium","gaps":["Mechanism by which DOPEY1 promotes p53 degradation via USP7/TRIP12 not resolved","Relationship between this nuclear/oncogenic role and the cytoplasmic trafficking function unclear","Single lab"]},{"year":2025,"claim":"The cellular range of DOP1A in the oligodendrocyte lineage was unclear; expression in OPCs and mature oligodendrocytes was established along with a differentiation/mRNA-trafficking defect.","evidence":"Immunolabeling with lineage markers and Mbp mRNA localization analysis in the VF rat loss-of-function model","pmids":["41067867"],"confidence":"Medium","gaps":["Molecular link between trafficking machinery and Mbp mRNA localization not defined","No in vitro mechanistic reconstitution"]},{"year":2026,"claim":"Whether DOP1A acts in lipid homeostasis beyond vesicle transport was unknown; this work showed mTOR-controlled relocalization to nuclear pore complexes where Dop1a binds AGPAT2 to suppress phospholipid synthesis and safeguard cell division.","evidence":"Live-cell localization, Dop1a-AGPAT2 Co-IP, loss-of-function with lipidomic and cell cycle readouts, and mTOR inhibitor treatment","pmids":["42164854"],"confidence":"Medium","gaps":["Mechanism of LPA-triggered relocalization to NPCs not resolved","How AGPAT2 binding suppresses phospholipid synthesis mechanistically unclear","Single lab"]},{"year":null,"claim":"How DOP1A's distinct roles — kinesin-1-coupled membrane transport, nuclear lipid homeostasis, and p53 regulation — are coordinated within one protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model connecting cytoplasmic adaptor and nuclear functions","No structural data on domain organization","Cargo and substrate repertoire incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3]}],"complexes":["Dopey1-Mon2 complex"],"partners":["MON2","KIF5/KINESIN-1","AGPAT2","USP7","TRIP12"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5JWR5","full_name":"Protein DOP1A","aliases":[],"length_aa":2465,"mass_kda":277.4,"function":"May be involved in protein traffic between late Golgi and early endosomes","subcellular_location":"Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q5JWR5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DOP1A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DOP1A","total_profiled":1310},"omim":[{"mim_id":"616823","title":"DOP1 LEUCINE ZIPPER-LIKE PROTEIN A; DOP1A","url":"https://www.omim.org/entry/616823"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DOP1A"},"hgnc":{"alias_symbol":["dJ202D23.2"],"prev_symbol":["KIAA1117","DOPEY1"]},"alphafold":{"accession":"Q5JWR5","domains":[{"cath_id":"-","chopping":"1619-1803","consensus_level":"medium","plddt":78.3572,"start":1619,"end":1803},{"cath_id":"1.25.40","chopping":"2-177","consensus_level":"medium","plddt":89.1058,"start":2,"end":177}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5JWR5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5JWR5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5JWR5-F1-predicted_aligned_error_v6.png","plddt_mean":66.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DOP1A","jax_strain_url":"https://www.jax.org/strain/search?query=DOP1A"},"sequence":{"accession":"Q5JWR5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5JWR5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5JWR5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5JWR5"}},"corpus_meta":[{"pmid":"31324769","id":"PMC_31324769","title":"Dopey1-Mon2 complex binds to dual-lipids and recruits kinesin-1 for membrane trafficking.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31324769","citation_count":29,"is_preprint":false},{"pmid":"24863653","id":"PMC_24863653","title":"The VF rat with abnormal myelinogenesis has a mutation in Dopey1.","date":"2014","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/24863653","citation_count":15,"is_preprint":false},{"pmid":"36028345","id":"PMC_36028345","title":"Genomic analyses of claw disorders in Holstein cows: Genetic parameters, trait associations, and genome-wide associations considering interactions of SNP and heat stress.","date":"2022","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/36028345","citation_count":13,"is_preprint":false},{"pmid":"39939725","id":"PMC_39939725","title":"Helicobacter pylori activates DOPEY1 to promote p53 degradation through the USP7/TRIP12 axis in gastric tumorigenesis.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/39939725","citation_count":5,"is_preprint":false},{"pmid":"25424701","id":"PMC_25424701","title":"Diagnostic significance of alternative splice variants of REST and DOPEY1 in the peripheral blood of patients with breast cancer.","date":"2014","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25424701","citation_count":5,"is_preprint":false},{"pmid":"41252186","id":"PMC_41252186","title":"Removal of developmentally regulated microexons has a minimal impact on larval zebrafish brain morphology and function.","date":"2025","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/41252186","citation_count":4,"is_preprint":false},{"pmid":"38818041","id":"PMC_38818041","title":"Whole exome sequencing identified a homozygous novel variant in DOP1A gene in the Pakistan family with neurodevelopmental disabilities: case report and literature review.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38818041","citation_count":1,"is_preprint":false},{"pmid":"42164854","id":"PMC_42164854","title":"The mTOR-Dop1a-Agpat2 axis regulates nuclear phospholipid homeostasis.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/42164854","citation_count":0,"is_preprint":false},{"pmid":"41067867","id":"PMC_41067867","title":"Impaired maturation and differentiation of oligodendrocytes in the vacuole formation myelin mutant rat.","date":"2025","source":"Veterinary pathology","url":"https://pubmed.ncbi.nlm.nih.gov/41067867","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6702,"output_tokens":1764,"usd":0.023283,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8603,"output_tokens":2517,"usd":0.05297,"stage2_stop_reason":"end_turn"},"total_usd":0.076253,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"Dopey1 and Mon2 assemble into a complex that localizes to the Golgi, endolysosome, and ER exit sites; Golgi localization of Dopey1 requires binding to phosphatidylinositol-4-phosphate (PI4P), while Mon2 localization requires phosphatidic acid (PA). The N-terminus of Dopey1 further interacts with kinesin-1, and the Dopey1-Mon2 complex functions as a dual-lipid-regulated cargo adaptor to recruit kinesin-1 to secretory and endocytic organelles for centrifugally biased bidirectional transport.\",\n      \"method\": \"Co-immunoprecipitation, lipid-binding assays, co-localization imaging, organelle fractionation, functional transport assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, lipid-binding assays, multiple orthogonal methods including localization and transport functional readouts in a single rigorous study\",\n      \"pmids\": [\"31324769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A nonsense mutation in Dopey1 (rat ortholog of DOP1A) causes hypomyelination and periaxonal vacuole formation in the VF rat; DOPEY1 protein is expressed in neurons and oligodendrocytes, and its loss leads to accumulation of myelin components (proteolipid protein and myelin-associated glycoprotein) in the oligodendrocyte cell body, implicating Dopey1 in intracellular trafficking of myelin components.\",\n      \"method\": \"Genetic mapping, Sanger sequencing, immunohistochemistry, Western blot, mRNA expression analysis\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function rat model with defined cellular phenotype (myelin component accumulation), multiple methods but single lab\",\n      \"pmids\": [\"24863653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"H. pylori infection upregulates DOPEY1 expression via a CagA-dependent pathway; DOPEY1 interacts with USP7 and TRIP12, and this complex promotes p53 degradation. DOPEY1 silencing reverses p53 degradation, and USP7 overexpression rescues p53 degradation in DOPEY1-silenced cells, placing DOPEY1 upstream of the USP7/TRIP12 axis in p53 regulation.\",\n      \"method\": \"Liquid chromatography-mass spectrometry (interactome), co-immunoprecipitation, siRNA knockdown, overexpression rescue, mouse tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP confirmed by LC-MS interactome, functional rescue experiment, in vivo tumor model; single lab\",\n      \"pmids\": [\"39939725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Under mTOR signaling control, a shortage of lysophosphatidic acid (LPA) triggers rapid relocalization of Dop1a to nuclear pore complexes (NPCs), where Dop1a binds AGPAT2 and suppresses phospholipid (PL) synthesis. Loss of Dop1a leads to elevated PL production, nuclear lipid droplet formation, and nuclear accumulation of CDK2, impairing cell cycle entry; thus Dop1a safeguards cell division by regulating nuclear membrane PL homeostasis.\",\n      \"method\": \"Live-cell imaging/localization assay, co-immunoprecipitation (Dop1a-AGPAT2), knockout/loss-of-function with lipidomic and cell cycle readouts, mTOR inhibitor treatment\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments linked to functional consequence, Co-IP of binding partner, loss-of-function with multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"42164854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DOP1A protein is expressed in oligodendrocyte progenitor cells (OPCs) as well as mature oligodendrocytes in the rat CNS; DOP1A dysfunction (via nonsense mutation) causes impaired differentiation and maturation of oligodendrocyte-lineage cells and disrupted intracellular trafficking of myelin basic protein (Mbp) mRNAs in oligodendrocytes, resulting in hypomyelination.\",\n      \"method\": \"Immunolabeling (anti-APC/CC1, transcription factor markers), mRNA localization analysis, VF rat loss-of-function model\",\n      \"journal\": \"Veterinary Pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotype with multiple marker readouts in a genetic loss-of-function model; single lab, no in vitro mechanistic reconstitution\",\n      \"pmids\": [\"41067867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Removal of a microexon in dop1a in zebrafish (using CRISPR/Cas9) produces mild neural phenotypes in larval brain activity, establishing that the microexon contributes to DOP1A function during neurodevelopment.\",\n      \"method\": \"CRISPR/Cas9 microexon deletion in zebrafish, larval brain activity imaging and behavioral assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (CRISPR KO), mild phenotype, no molecular mechanism defined for the microexon's contribution\",\n      \"pmids\": [\"41252186\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DOP1A (DOPEY1) functions as a dual-lipid-regulated cargo adaptor: in complex with Mon2, it binds PI4P (via Dopey1) and phosphatidic acid (via Mon2) at Golgi and endocytic organelles, recruits kinesin-1 via its N-terminus to drive centrifugally biased vesicle transport, and is required for myelin component trafficking in oligodendrocytes; additionally, under mTOR signaling, DOP1A relocates to nuclear pore complexes where it binds AGPAT2 to suppress phospholipid synthesis and safeguard cell division, and in the context of H. pylori infection it interacts with USP7 and TRIP12 to promote p53 degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DOP1A (DOPEY1) is a dual-lipid-regulated cargo adaptor that couples organelle membranes to microtubule-based transport: in complex with Mon2 it localizes to the Golgi, endolysosomes, and ER exit sites, where Dopey1 binds PI4P and Mon2 binds phosphatidic acid, and the Dopey1 N-terminus recruits kinesin-1 to drive centrifugally biased bidirectional vesicle transport [#0]. This trafficking function is required in the nervous system, where loss-of-function causes mislocalization of myelin components — proteolipid protein and myelin-associated glycoprotein accumulate in the oligodendrocyte cell body and myelin basic protein mRNA fails to be properly trafficked — producing impaired oligodendrocyte differentiation and hypomyelination [#1, #4]. Beyond its trafficking role, DOP1A acts in lipid homeostasis at the nuclear envelope: under mTOR control, a shortage of lysophosphatidic acid relocalizes Dop1a to nuclear pore complexes where it binds AGPAT2 to suppress phospholipid synthesis, and its loss elevates phospholipid production, drives nuclear lipid droplet formation, and impairs cell cycle entry through nuclear CDK2 accumulation [#3]. DOP1A is also co-opted during Helicobacter pylori infection, where CagA-dependent upregulation of DOPEY1 enables it to act with USP7 and TRIP12 to promote p53 degradation [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Whether DOP1A has a defined cellular function was unknown; a rat loss-of-function model established its role in intracellular trafficking of myelin components in oligodendrocytes.\",\n      \"evidence\": \"Genetic mapping and nonsense mutation in the VF rat with immunohistochemistry and Western blot for myelin proteins\",\n      \"pmids\": [\"24863653\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No molecular mechanism for how DOPEY1 mediates myelin component trafficking\",\n        \"No identification of binding partners or cargo at this stage\",\n        \"Phenotype defined in rat ortholog only\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The biochemical basis of DOP1A trafficking activity was undefined; this work established the Dopey1-Mon2 complex as a dual-lipid-regulated cargo adaptor that recruits kinesin-1 to secretory and endocytic organelles.\",\n      \"evidence\": \"Reciprocal Co-IP, lipid-binding assays, co-localization imaging, organelle fractionation, and functional transport assays\",\n      \"pmids\": [\"31324769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cargo identity for the kinesin-1-driven transport not defined\",\n        \"Link between this adaptor mechanism and the myelin trafficking phenotype not directly demonstrated\",\n        \"Structural basis of PI4P and PA recognition not resolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether DOP1A is co-opted in disease was unknown; H. pylori work placed DOPEY1 upstream of a USP7/TRIP12 axis that degrades p53.\",\n      \"evidence\": \"LC-MS interactome, reciprocal Co-IP, siRNA knockdown, overexpression rescue, and mouse tumor model\",\n      \"pmids\": [\"39939725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which DOPEY1 promotes p53 degradation via USP7/TRIP12 not resolved\",\n        \"Relationship between this nuclear/oncogenic role and the cytoplasmic trafficking function unclear\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The cellular range of DOP1A in the oligodendrocyte lineage was unclear; expression in OPCs and mature oligodendrocytes was established along with a differentiation/mRNA-trafficking defect.\",\n      \"evidence\": \"Immunolabeling with lineage markers and Mbp mRNA localization analysis in the VF rat loss-of-function model\",\n      \"pmids\": [\"41067867\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular link between trafficking machinery and Mbp mRNA localization not defined\",\n        \"No in vitro mechanistic reconstitution\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Whether DOP1A acts in lipid homeostasis beyond vesicle transport was unknown; this work showed mTOR-controlled relocalization to nuclear pore complexes where Dop1a binds AGPAT2 to suppress phospholipid synthesis and safeguard cell division.\",\n      \"evidence\": \"Live-cell localization, Dop1a-AGPAT2 Co-IP, loss-of-function with lipidomic and cell cycle readouts, and mTOR inhibitor treatment\",\n      \"pmids\": [\"42164854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of LPA-triggered relocalization to NPCs not resolved\",\n        \"How AGPAT2 binding suppresses phospholipid synthesis mechanistically unclear\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DOP1A's distinct roles — kinesin-1-coupled membrane transport, nuclear lipid homeostasis, and p53 regulation — are coordinated within one protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unifying model connecting cytoplasmic adaptor and nuclear functions\",\n        \"No structural data on domain organization\",\n        \"Cargo and substrate repertoire incompletely defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"Dopey1-Mon2 complex\"\n    ],\n    \"partners\": [\n      \"MON2\",\n      \"KIF5/kinesin-1\",\n      \"AGPAT2\",\n      \"USP7\",\n      \"TRIP12\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}