{"gene":"TASOR","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2015,"finding":"TASOR is a core subunit of the HUSH (human silencing hub) complex, together with MPP8 and Periphilin. Loss of HUSH components, including TASOR, results in decreased H3K9me3 at endogenous genomic loci and at retroviruses integrated into heterochromatin. The HUSH complex is recruited to H3K9me3-rich genomic loci, where it recruits the methyltransferase SETDB1 for further H3K9me3 deposition to maintain transcriptional silencing.","method":"Forward genetic screen in near-haploid KBM7 cells, loss-of-function analysis, chromatin immunoprecipitation","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — forward genetic screen plus ChIP showing H3K9me3 loss, replicated across subsequent studies","pmids":["26022416"],"is_preprint":false},{"year":2017,"finding":"TASOR (as part of the HUSH complex) selectively binds evolutionarily young, full-length L1 elements located in transcriptionally permissive euchromatic environments and promotes H3K9me3 deposition for transcriptional silencing. HUSH-mediated silencing events within introns of transcriptionally active genes lead to downregulation of host gene expression in a HUSH- and L1-dependent manner.","method":"CRISPR-Cas9 genome-wide screen, ChIP-seq, loss-of-function in two distinct human cell lines","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen plus ChIP-seq, two distinct cell lines, multiple orthogonal methods","pmids":["29211708"],"is_preprint":false},{"year":2018,"finding":"HIV-2/SIV Vpx protein associates with the HUSH complex and induces proteasomal degradation of TASOR (and other HUSH subunits) through recruitment of the DCAF1-CUL4A/B E3 ubiquitin ligase, independently of SAMHD1 antagonism. This degradation reactivates HIV latent proviruses and increases LINE-1 ORF1p levels.","method":"Proteomic screen, co-immunoprecipitation, proteasome inhibitor rescue, knockdown rescue experiments, HIV latency reactivation assay","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated independently in two concurrent papers (PMID:29891865, PMID:30297740) using co-IP, proteasome inhibition, and functional assays","pmids":["29891865","30297740"],"is_preprint":false},{"year":2018,"finding":"NP220 recruits the HUSH complex (including TASOR) along with SETDB1 and histone deacetylases HDAC1 and HDAC4 to silence unintegrated retroviral DNA; TASOR/HUSH is required for this silencing as shown by CRISPR knockout de-repression.","method":"Genome-wide CRISPR-Cas9 screen, chromatin immunoprecipitation, knockout validation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen, ChIP validation, and functional knockouts in same study","pmids":["30487602"],"is_preprint":false},{"year":2020,"finding":"TASOR is the central scaffolding subunit of the HUSH complex; it bears a catalytically-inactive (pseudo-)PARP domain that is necessary for targeted H3K9me3 deposition and transgene repression, independently of overall complex assembly. TASOR associates with RNA processing components. The modular architecture of HUSH resembles the yeast RNA-induced transcriptional silencing (RITS) complex.","method":"Biochemical reconstitution, structure-function mutagenesis of TASOR domains, H3K9me3 ChIP-seq, transgene repression reporter assay, co-immunoprecipitation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — domain mutagenesis combined with ChIP-seq and functional reporter assay in a single study with multiple orthogonal approaches","pmids":["33009411"],"is_preprint":false},{"year":2020,"finding":"A crystal structure of the Periphilin-TASOR minimal core complex shows that Periphilin forms an α-helical homodimer bound by a single TASOR molecule. Residues required for TASOR binding and Periphilin aggregation are required for HUSH-dependent silencing and genome-wide H3K9me3 deposition.","method":"X-ray crystallography, mutagenesis, H3K9me3 ChIP, silencing reporter assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with mutagenesis and functional silencing assays in one study","pmids":["32976585"],"is_preprint":false},{"year":2021,"finding":"The N-terminal PARP-like domain of TASOR is involved in DCAF1 binding (but not in Vpx binding). TASOR can interact with DCAF1 in the absence of Vpx, and this interaction is stabilized by Vpx to form a ternary TASOR-Vpx-DCAF1 complex that leads to TASOR ubiquitination and degradation.","method":"Co-immunoprecipitation, Vpx point mutant analysis, domain mapping, functional HIV reporter assay","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mutants and Vpx point mutants, functional validation, single lab","pmids":["34699574"],"is_preprint":false},{"year":2022,"finding":"TASOR interacts with the CCR4-NOT complex scaffold CNOT1 (identified by yeast two-hybrid screen), and TASOR and CNOT1 synergistically repress HIV LTR-driven expression. TASOR also interacts with the RNA exosome and with RNA Polymerase II predominantly in its elongating state, and facilitates the association of RNA degradation proteins with RNA Pol II at transcriptional centers.","method":"Yeast two-hybrid screen, co-immunoprecipitation, HIV LTR reporter assay, RNA Pol II co-IP, immunofluorescence at transcriptional centers","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast 2-hybrid plus co-IP and functional reporter assays, single lab, multiple orthogonal methods","pmids":["35013187"],"is_preprint":false},{"year":2022,"finding":"TASOR is phosphorylated at T819 by a Cyclin/CDK1 complex, especially in cells arrested in early mitosis. However, this phosphorylation does not correlate with TASOR-mediated HIV-1 silencing, as T819A and T819E TASOR mutants repress HIV-1 LTR-driven expression similarly to wild-type TASOR.","method":"Phospho-specific antibody, nocodazole/etoposide cell cycle arrest, CDK1 inhibitor, TASOR point mutant overexpression in HIV-1 latency model","journal":"Retrovirology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — phospho-antibody detection plus functional mutant assay, but single lab and limited mechanistic follow-up on the phosphorylation's positive role","pmids":["36309692"],"is_preprint":false},{"year":2023,"finding":"TASOR's DUF3715 domain adopts a pseudo-PARP (RDTS) structure with extensive structural homology to TEX15's DUF3715 domain. The DUF3715 domain from divergent TEX15 sequences can functionally substitute the DUF3715 domain of TASOR and mediate transposon silencing, establishing a conserved functional role for this domain in RNA-directed transposon silencing.","method":"Structural homology analysis, functional domain-swap experiments, transposon silencing reporter assay","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — structural analysis combined with functional domain-swap experiments, single lab","pmids":["37433650"],"is_preprint":false},{"year":2023,"finding":"The HUSH complex (including TASOR) interacts with the transcription termination factor WDR82 and accumulates at sites of high RNAPII occupancy including long exons and transcription termination sites in a WDR82- and CPSF-dependent manner, demonstrating co-transcriptional chromatin targeting for genome surveillance.","method":"Co-immunoprecipitation, ChIP-seq, genetic epistasis with WDR82/CPSF knockouts, genomic rearrangement at Sox2 locus","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, ChIP-seq, epistatic knockouts, and natural genomic rearrangement experiment, multiple orthogonal approaches in single study","pmids":["37164018"],"is_preprint":false},{"year":2023,"finding":"HUSH complex (MPP8 and TASOR subunits) interacts with the leading-strand DNA polymerase Pol ε and contributes to asymmetric H3K9me3 distribution at replication forks (preferentially onto leading strands at LINE-1 elements). TASOR mutants with reduced Pol ε interaction show compromised H3K9me3 asymmetry and increased LINE expression.","method":"Co-immunoprecipitation, H3K9me3 strand-specific ChIP, TASOR interaction mutants, POLE3/POLE4 and MPP8/TASOR knockouts","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP with Pol ε, strand-specific ChIP, multiple loss-of-function models, and interaction-defective TASOR mutants, multiple orthogonal methods in one study","pmids":["37938774"],"is_preprint":false},{"year":2024,"finding":"AlphaFold3 modeling of the MPP8-TASOR complex predicts that a SPOC domain and a domain with a novel fold in TASOR form extended interaction interfaces with the MPP8 C-terminal domain (ankyrin repeats + PINIT-like domain). Point mutations at these predicted interfaces resulted in loss of HUSH-dependent transcriptional repression, validating the structural model.","method":"X-ray crystallography (MPP8 CTD), AlphaFold3 structural modeling, point mutagenesis, cell-based transcriptional repression reporter assay","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — crystal structure of MPP8 CTD with AlphaFold3 modeling and mutagenesis validation, single lab","pmids":["39638237"],"is_preprint":false},{"year":2024,"finding":"TASOR loss in naive pluripotent stem cells triggers replication stress, disrupts H3K9me3 heterochromatin, and impairs silencing of LINE-1 transposable elements. Unscheduled L1 expression upon TASOR loss activates an innate immune response (MAVS pathway) leading to cell death specifically in cells exiting naive pluripotency; this is rescued by caspase inhibition or MAVS deletion.","method":"CRISPR knockout, H3K9me3 ChIP, LINE-1 expression analysis, caspase inhibitor treatment, MAVS genetic deletion, pluripotency transition assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockouts with multiple functional readouts and epistatic rescue, single lab","pmids":["39453814"],"is_preprint":false},{"year":2024,"finding":"HuSH (HUSH) complex centered on TASOR and a second paralogous HuSH2 complex centered on TASOR2 localize to distinct, non-overlapping genomic loci; HUSH/TASOR represses LINE-1 retrotransposons. MPP8 interaction with TASOR is disrupted by specific amino acid substitutions guided by in silico structural predictions, and the relative quantities of HuSH complexes regulate LINE-1 activity.","method":"ChIP-seq, in silico protein structure prediction, mutagenesis of MPP8-TASOR interface, LINE-1 reporter assay, CRISPR knockout","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, structural modeling with experimental mutagenesis validation, functional reporter assay, single lab","pmids":["39489739"],"is_preprint":false},{"year":2025,"finding":"Vpx-mediated degradation of TASOR leads to increased LINE-1 activity, which in turn activates innate immune sensing; ISG induction by Vpx-mediated TASOR degradation relies on both RNA sensing (MAVS signaling) and DNA sensing (cGAS/STING signaling).","method":"Vpx mutant analysis, transcriptomic analysis, TASOR degradation experiments, MAVS and cGAS/STING pathway inhibition","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Vpx mutant dissection with pathway-specific inhibitors, single lab, multiple readouts","pmids":["42190982"],"is_preprint":false},{"year":2025,"finding":"Periphilin is the major RNA-binding component of the HUSH complex; its N-terminal domain is essential for both RNA binding and HUSH function. Artificial tethering of Periphilin to a HUSH-insensitive nascent transcript enables HUSH-dependent silencing of that transcript, establishing that Periphilin's RNA binding initiates HUSH silencing. Periphilin's RNA binding is independent of its interaction with TASOR or MPP8.","method":"Unbiased RNA-binding assay, domain truncation analysis, tethering reporter assay, mutagenesis of Periphilin NTD","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased RNA-binding identification, domain mapping, and tethering functional assay, single lab; directly informs TASOR complex mechanism","pmids":["39658355"],"is_preprint":false},{"year":2025,"finding":"In mouse embryonic stem cells, deficiency of both MPP8 and TASOR (double mutant) locks cells in pluripotent state even upon differentiation stimuli, and decreases expression of adhesion-related genes (keratins 18 and 19); ectopic co-expression of keratins 18 and 19 rescues the exit-from-pluripotency defect.","method":"CRISPR-based knockout, pluripotency exit assay, gene expression analysis, ectopic expression rescue","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic double knockout with functional rescue by downstream effectors, single lab","pmids":["41291012"],"is_preprint":false},{"year":2024,"finding":"PRC1.6 components L3MBTL2 and MGA contribute to HUSH complex-mediated provirus silencing in a promoter-specific manner. PRC1.6 and HUSH complexes co-localize on chromatin primarily at active promoters, and PRC1.6 binding at a subset of HUSH-silenced genes is dependent on core HUSH component MPP8.","method":"Proximity labeling (C-BERST/dCas9-APEX2), forward genetic screen, ChIP-seq co-localization, MPP8-dependent PRC1.6 binding analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling screen with ChIP-seq validation and forward genetic screen confirmation, preprint, single lab","pmids":["39026796"],"is_preprint":true}],"current_model":"TASOR is the central scaffolding subunit of the HUSH (human silencing hub) complex, which it assembles with MPP8 and Periphilin via a catalytically-inactive pseudo-PARP (RDTS/DUF3715) domain; the complex recruits SETDB1 to deposit H3K9me3 at LINE-1 retrotransposons, integrated retroviruses, and repetitive transgenes, with RNA-mediated targeting initiated by Periphilin's nascent-RNA binding, co-transcriptional surveillance coupled to RNAPII termination machinery (WDR82/CPSF), asymmetric H3K9me3 inheritance facilitated by interaction with leading-strand polymerase Pol ε during replication, and post-transcriptional repression involving the CNOT1 RNA deadenylase complex and RNA exosome; HIV-2/SIV Vpx counteracts TASOR by forming a ternary complex with DCAF1 to drive proteasomal degradation of TASOR, whose loss de-represses LINE-1s and activates innate immune sensing via MAVS and cGAS/STING."},"narrative":{"mechanistic_narrative":"TASOR is the central scaffolding subunit of the HUSH (human silencing hub) complex, which it assembles with MPP8 and Periphilin to deposit H3K9me3 heterochromatin and transcriptionally silence retroviruses, repetitive transgenes, and evolutionarily young, full-length LINE-1 retrotransposons residing in euchromatin [PMID:26022416, PMID:29211708, PMID:33009411]. TASOR organizes the complex through defined interaction interfaces—an N-terminal catalytically-inactive pseudo-PARP (DUF3715/RDTS) domain required for targeted H3K9me3 deposition and silencing, a SPOC and novel-fold module engaging the MPP8 C-terminal domain, and a minimal core that binds a Periphilin homodimer—and through these contacts recruits the methyltransferase SETDB1 to establish and maintain silencing [PMID:33009411, PMID:32976585, PMID:37433650, PMID:39638237, PMID:39489739]. Targeting is RNA-directed and co-transcriptional: Periphilin's N-terminal domain binds nascent transcripts to initiate silencing [PMID:39658355], while TASOR couples the complex to elongating RNA Polymerase II and to RNA-degradation machinery including the CNOT1/CCR4-NOT deadenylase complex and the RNA exosome, and accumulates at sites of high RNAPII occupancy and transcription termination through the WDR82/CPSF termination machinery [PMID:35013187, PMID:37164018]. During replication, HUSH interacts with leading-strand polymerase Pol ε to propagate asymmetric H3K9me3 onto leading strands at LINE-1 elements [PMID:37938774]. Loss of TASOR de-represses LINE-1s, triggering replication stress and activating innate immune sensing via MAVS and cGAS/STING [PMID:39453814, PMID:42190982]. The HIV-2/SIV accessory protein Vpx antagonizes this pathway by stabilizing a ternary complex between TASOR's N-terminal PARP-like domain, DCAF1, and the CUL4 E3 ligase to drive proteasomal degradation of TASOR, reactivating latent proviruses [PMID:29891865, PMID:30297740, PMID:34699574].","teleology":[{"year":2015,"claim":"Established that TASOR is a core subunit of a previously unknown silencing complex that maintains H3K9me3 heterochromatin, answering how certain integrated retroviruses and genomic loci are kept transcriptionally silent.","evidence":"Forward genetic screen in haploid KBM7 cells with ChIP for H3K9me3","pmids":["26022416"],"confidence":"High","gaps":["Did not define how HUSH is targeted to specific loci","Did not assign TASOR a distinct molecular function within the complex"]},{"year":2017,"claim":"Identified the principal endogenous targets of HUSH as young, full-length LINE-1 elements in permissive euchromatin, explaining the complex's role in genome surveillance and its impact on host gene expression.","evidence":"Genome-wide CRISPR screen and ChIP-seq in two human cell lines","pmids":["29211708"],"confidence":"High","gaps":["Did not establish how young L1 elements are recognized","Mechanism of co-transcriptional targeting unresolved"]},{"year":2018,"claim":"Revealed that HIV-2/SIV Vpx counteracts HUSH by inducing proteasomal degradation of TASOR via DCAF1-CUL4, linking the complex to retroviral latency and host antiviral defense.","evidence":"Proteomic screen, co-IP, proteasome inhibitor rescue, and HIV latency reactivation assays (two concurrent papers)","pmids":["29891865","30297740"],"confidence":"High","gaps":["Did not map the TASOR domains engaged by Vpx/DCAF1","Did not address whether degradation is selective for specific HUSH functions"]},{"year":2018,"claim":"Showed HUSH/TASOR is recruited by NP220 to silence unintegrated retroviral DNA together with SETDB1 and HDACs, broadening the range of foreign DNA the complex restricts.","evidence":"Genome-wide CRISPR screen, ChIP, and knockout validation","pmids":["30487602"],"confidence":"High","gaps":["Did not define TASOR's direct contribution versus other recruited factors","Generality of NP220-dependent recruitment unclear"]},{"year":2020,"claim":"Defined TASOR as the central scaffold whose pseudo-PARP domain is required for H3K9me3 deposition independent of complex assembly, and resolved the Periphilin-TASOR core interface, providing the architectural basis of HUSH.","evidence":"Biochemical reconstitution, domain mutagenesis, ChIP-seq, reporter assays, and X-ray crystallography of the Periphilin-TASOR core","pmids":["33009411","32976585"],"confidence":"High","gaps":["Did not establish the catalytic or binding function of the pseudo-PARP domain","Did not resolve the TASOR-MPP8 interface"]},{"year":2021,"claim":"Mapped TASOR's N-terminal PARP-like domain as the DCAF1-binding region and showed TASOR-DCAF1 association is constitutive but Vpx-stabilized into a degradative ternary complex, clarifying the molecular logic of Vpx antagonism.","evidence":"Co-IP with domain and Vpx point mutants plus HIV reporter assay","pmids":["34699574"],"confidence":"Medium","gaps":["Single lab","Physiological role of basal TASOR-DCAF1 interaction unknown"]},{"year":2022,"claim":"Connected TASOR to post-transcriptional repression by demonstrating interactions with CNOT1, the RNA exosome, and elongating RNA Pol II, indicating HUSH couples chromatin silencing to RNA degradation at transcription centers.","evidence":"Yeast two-hybrid screen, co-IP, RNA Pol II co-IP, and HIV LTR reporter assays","pmids":["35013187"],"confidence":"Medium","gaps":["Single lab","Direct versus indirect nature of RNA-degradation coupling not fully resolved"]},{"year":2022,"claim":"Identified CDK1-mediated phosphorylation of TASOR at T819 in mitosis, but showed it is dispensable for HIV-1 silencing, indicating this modification is not required for the repressive function tested.","evidence":"Phospho-specific antibody, cell cycle arrest, CDK1 inhibition, and T819 point mutant assays in an HIV-1 latency model","pmids":["36309692"],"confidence":"Medium","gaps":["Positive functional role of T819 phosphorylation, if any, undefined","Single lab and limited mechanistic follow-up"]},{"year":2023,"claim":"Established the DUF3715/pseudo-PARP domain as a conserved RNA-directed silencing module by showing TEX15's homologous domain functionally substitutes in TASOR, deepening understanding of how this domain enables transposon silencing.","evidence":"Structural homology analysis and domain-swap transposon silencing assays","pmids":["37433650"],"confidence":"Medium","gaps":["Single lab","Biochemical activity contributed by the domain remains undefined"]},{"year":2023,"claim":"Showed HUSH co-transcriptional targeting requires the termination factor WDR82 and CPSF, with the complex accumulating at high-RNAPII-occupancy regions, explaining how silencing is directed to actively transcribed repetitive loci.","evidence":"Reciprocal co-IP, ChIP-seq, epistatic WDR82/CPSF knockouts, and a Sox2 genomic rearrangement experiment","pmids":["37164018"],"confidence":"High","gaps":["How the RNA signal is converted to chromatin recruitment unresolved","TASOR-specific role within this targeting not isolated"]},{"year":2023,"claim":"Demonstrated HUSH interacts with leading-strand polymerase Pol ε to propagate asymmetric H3K9me3 at replication forks, providing a mechanism for heritable maintenance of LINE-1 silencing through replication.","evidence":"Co-IP with Pol ε, strand-specific H3K9me3 ChIP, POLE3/POLE4 and MPP8/TASOR knockouts, and interaction-defective TASOR mutants","pmids":["37938774"],"confidence":"High","gaps":["Structural basis of TASOR-Pol ε interaction not defined","Lagging-strand restoration mechanism unaddressed"]},{"year":2024,"claim":"Resolved the TASOR-MPP8 interface using crystallography and AlphaFold3 modeling validated by mutagenesis, completing the structural map of HUSH subunit contacts required for repression.","evidence":"X-ray crystallography of MPP8 CTD, AlphaFold3 modeling, point mutagenesis, and reporter assays","pmids":["39638237"],"confidence":"Medium","gaps":["Model-derived interfaces partly predictive rather than experimentally resolved","Single lab"]},{"year":2024,"claim":"Revealed a paralogous HuSH2 complex centered on TASOR2 occupying distinct genomic loci, with TASOR-HUSH dedicated to LINE-1 repression and HUSH stoichiometry tuning L1 activity.","evidence":"ChIP-seq, in silico structural prediction, MPP8-TASOR interface mutagenesis, and LINE-1 reporter assays","pmids":["39489739"],"confidence":"Medium","gaps":["Functional division of labor between HUSH and HuSH2 incompletely defined","Single lab"]},{"year":2024,"claim":"Connected TASOR loss to physiological consequences by showing de-repressed LINE-1 triggers replication stress and MAVS-dependent innate immune death during exit from naive pluripotency.","evidence":"CRISPR knockout, H3K9me3 ChIP, L1 expression analysis, caspase inhibition, and MAVS deletion in stem cells","pmids":["39453814"],"confidence":"Medium","gaps":["Single lab","Whether replication stress is a direct or downstream consequence of L1 activation unresolved"]},{"year":2024,"claim":"Linked HUSH to PRC1.6 components L3MBTL2 and MGA at active promoters, with promoter-specific MPP8-dependent PRC1.6 recruitment, expanding the repressive cofactor network.","evidence":"Proximity labeling (dCas9-APEX2), forward genetic screen, and ChIP-seq co-localization (preprint)","pmids":["39026796"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Direct TASOR contribution to PRC1.6 recruitment not isolated"]},{"year":2025,"claim":"Demonstrated that Vpx-driven TASOR degradation activates both RNA (MAVS) and DNA (cGAS/STING) innate sensing pathways via increased LINE-1 activity, integrating HUSH antagonism with antiviral signaling.","evidence":"Vpx mutant dissection, transcriptomics, and MAVS and cGAS/STING pathway inhibition","pmids":["42190982"],"confidence":"Medium","gaps":["Single lab","Relative contributions of RNA versus DNA sensing not quantified"]},{"year":2025,"claim":"Established Periphilin as the RNA-binding initiator of HUSH silencing, showing its N-terminal domain binds nascent transcripts and that tethering Periphilin suffices to silence a HUSH-insensitive transcript, defining the upstream targeting trigger.","evidence":"Unbiased RNA-binding assay, domain truncation, Periphilin NTD mutagenesis, and tethering reporter assay","pmids":["39658355"],"confidence":"Medium","gaps":["Single lab","How Periphilin RNA recognition is converted to TASOR/MPP8-dependent chromatin modification unresolved"]},{"year":2025,"claim":"Showed combined MPP8/TASOR loss locks mouse ES cells in pluripotency by suppressing keratin 18/19 adhesion genes, with keratin re-expression rescuing differentiation, linking HUSH to a developmental gene-regulatory output.","evidence":"CRISPR double knockout, pluripotency exit assay, gene expression analysis, and ectopic keratin rescue","pmids":["41291012"],"confidence":"Medium","gaps":["Single lab","Mechanistic link between HUSH silencing and keratin regulation undefined"]},{"year":null,"claim":"The biochemical activity contributed by TASOR's pseudo-PARP domain and how nascent-RNA recognition by Periphilin is mechanistically transduced into TASOR-directed SETDB1 recruitment and H3K9me3 deposition remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No catalytic activity assigned to the pseudo-PARP domain","Step-wise coupling from RNA binding to chromatin modification not reconstituted","Full-complex structure with SETDB1 not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,5,12]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,10]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,1,11]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,10]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,6,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,15]}],"complexes":["HUSH complex"],"partners":["MPP8","PPHLN1","SETDB1","DCAF1","CNOT1","WDR82","POLE","RNA POL II"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UK61","full_name":"Protein TASOR","aliases":["CTCL tumor antigen se89-1","Retinoblastoma-associated protein RAP140","Transgene activation suppressor protein"],"length_aa":1670,"mass_kda":189.0,"function":"Core component of the HUSH complex, a multiprotein complex that specifically mediates epigenetic repression of mobile genetic elements, such as retroviruses and transposable elements (PubMed:26022416, PubMed:28581500, PubMed:29211708, PubMed:32976585, PubMed:33009411, PubMed:37433650). The HUSH complex represses LINE-1 (L1) retrotransposons that are still capable of transposition (PubMed:29211708, PubMed:32976585). Silencing events often occur within introns of transcriptionally active genes, and lead to the down-regulation of host gene expression (PubMed:29211708). The HUSH complex also represses exogenous retroviruses and synthetic transgenes (PubMed:26022416). The HUSH complex also represses expression of latent herpes simplex virus (PubMed:39589886). Mediates silencing of unintegrated retroviral DNA following recruitment by ZNF638: some part of the retroviral DNA formed immediately after infection remains unintegrated in the host genome and is transcriptionally repressed (PubMed:30487602). The HUSH complex is recruited to genomic loci rich in H3K9me3 and is required to maintain transcriptional silencing by promoting recruitment of SETDB1, a histone methyltransferase that mediates further deposition of H3K9me3, as well as MORC2, a chromatin remodeler that compacts chromatin (PubMed:26022416, PubMed:28581500). Within the HUSH complex, TASOR acts as the central scaffold which recruits MPHOSPH8 and PPHLN1 to mobile genetic elements and mediates association with SETDB1 and MORC2 (PubMed:32976585, PubMed:33009411, PubMed:39589886). The ability to silence mobile genetic elements plays a crucial role in early embryonic development: it is required to maintain epiblast cell fitness and cell division (By similarity)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q9UK61/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TASOR","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPC","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TASOR","total_profiled":1310},"omim":[{"mim_id":"621243","title":"TRANSCRIPTION ACTIVATION SUPPRESSOR FAMILY, MEMBER 2; TASOR2","url":"https://www.omim.org/entry/621243"},{"mim_id":"616661","title":"MORC FAMILY CW-TYPE ZINC FINGER PROTEIN 2; MORC2","url":"https://www.omim.org/entry/616661"},{"mim_id":"616493","title":"TRANSCRIPTION ACTIVATION REPRESSOR; TASOR","url":"https://www.omim.org/entry/616493"},{"mim_id":"614349","title":"ZINC FINGER PROTEIN 638; ZNF638","url":"https://www.omim.org/entry/614349"},{"mim_id":"611626","title":"M-PHASE PHOSPHOPROTEIN 8; MPHOSPH8","url":"https://www.omim.org/entry/611626"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TASOR"},"hgnc":{"alias_symbol":["se89-1","RAP140","KIAA1105","TASOR1"],"prev_symbol":["C3orf63","FAM208A"]},"alphafold":{"accession":"Q9UK61","domains":[{"cath_id":"3.90.228.10","chopping":"114-328","consensus_level":"high","plddt":89.408,"start":114,"end":328},{"cath_id":"2.40.290","chopping":"357-497","consensus_level":"high","plddt":80.7977,"start":357,"end":497},{"cath_id":"-","chopping":"543-580_605-622","consensus_level":"medium","plddt":63.8173,"start":543,"end":622},{"cath_id":"-","chopping":"1232-1319","consensus_level":"medium","plddt":85.6655,"start":1232,"end":1319},{"cath_id":"3.40.50.1010","chopping":"1325-1474","consensus_level":"medium","plddt":85.3409,"start":1325,"end":1474}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UK61","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UK61-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UK61-F1-predicted_aligned_error_v6.png","plddt_mean":56.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TASOR","jax_strain_url":"https://www.jax.org/strain/search?query=TASOR"},"sequence":{"accession":"Q9UK61","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UK61.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UK61/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UK61"}},"corpus_meta":[{"pmid":"29211708","id":"PMC_29211708","title":"Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/29211708","citation_count":273,"is_preprint":false},{"pmid":"26022416","id":"PMC_26022416","title":"GENE SILENCING. 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Loss of HUSH components, including TASOR, results in decreased H3K9me3 at endogenous genomic loci and at retroviruses integrated into heterochromatin. The HUSH complex is recruited to H3K9me3-rich genomic loci, where it recruits the methyltransferase SETDB1 for further H3K9me3 deposition to maintain transcriptional silencing.\",\n      \"method\": \"Forward genetic screen in near-haploid KBM7 cells, loss-of-function analysis, chromatin immunoprecipitation\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — forward genetic screen plus ChIP showing H3K9me3 loss, replicated across subsequent studies\",\n      \"pmids\": [\"26022416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TASOR (as part of the HUSH complex) selectively binds evolutionarily young, full-length L1 elements located in transcriptionally permissive euchromatic environments and promotes H3K9me3 deposition for transcriptional silencing. HUSH-mediated silencing events within introns of transcriptionally active genes lead to downregulation of host gene expression in a HUSH- and L1-dependent manner.\",\n      \"method\": \"CRISPR-Cas9 genome-wide screen, ChIP-seq, loss-of-function in two distinct human cell lines\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen plus ChIP-seq, two distinct cell lines, multiple orthogonal methods\",\n      \"pmids\": [\"29211708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HIV-2/SIV Vpx protein associates with the HUSH complex and induces proteasomal degradation of TASOR (and other HUSH subunits) through recruitment of the DCAF1-CUL4A/B E3 ubiquitin ligase, independently of SAMHD1 antagonism. This degradation reactivates HIV latent proviruses and increases LINE-1 ORF1p levels.\",\n      \"method\": \"Proteomic screen, co-immunoprecipitation, proteasome inhibitor rescue, knockdown rescue experiments, HIV latency reactivation assay\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated independently in two concurrent papers (PMID:29891865, PMID:30297740) using co-IP, proteasome inhibition, and functional assays\",\n      \"pmids\": [\"29891865\", \"30297740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NP220 recruits the HUSH complex (including TASOR) along with SETDB1 and histone deacetylases HDAC1 and HDAC4 to silence unintegrated retroviral DNA; TASOR/HUSH is required for this silencing as shown by CRISPR knockout de-repression.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen, chromatin immunoprecipitation, knockout validation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen, ChIP validation, and functional knockouts in same study\",\n      \"pmids\": [\"30487602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TASOR is the central scaffolding subunit of the HUSH complex; it bears a catalytically-inactive (pseudo-)PARP domain that is necessary for targeted H3K9me3 deposition and transgene repression, independently of overall complex assembly. TASOR associates with RNA processing components. The modular architecture of HUSH resembles the yeast RNA-induced transcriptional silencing (RITS) complex.\",\n      \"method\": \"Biochemical reconstitution, structure-function mutagenesis of TASOR domains, H3K9me3 ChIP-seq, transgene repression reporter assay, co-immunoprecipitation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — domain mutagenesis combined with ChIP-seq and functional reporter assay in a single study with multiple orthogonal approaches\",\n      \"pmids\": [\"33009411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A crystal structure of the Periphilin-TASOR minimal core complex shows that Periphilin forms an α-helical homodimer bound by a single TASOR molecule. Residues required for TASOR binding and Periphilin aggregation are required for HUSH-dependent silencing and genome-wide H3K9me3 deposition.\",\n      \"method\": \"X-ray crystallography, mutagenesis, H3K9me3 ChIP, silencing reporter assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with mutagenesis and functional silencing assays in one study\",\n      \"pmids\": [\"32976585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The N-terminal PARP-like domain of TASOR is involved in DCAF1 binding (but not in Vpx binding). TASOR can interact with DCAF1 in the absence of Vpx, and this interaction is stabilized by Vpx to form a ternary TASOR-Vpx-DCAF1 complex that leads to TASOR ubiquitination and degradation.\",\n      \"method\": \"Co-immunoprecipitation, Vpx point mutant analysis, domain mapping, functional HIV reporter assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mutants and Vpx point mutants, functional validation, single lab\",\n      \"pmids\": [\"34699574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TASOR interacts with the CCR4-NOT complex scaffold CNOT1 (identified by yeast two-hybrid screen), and TASOR and CNOT1 synergistically repress HIV LTR-driven expression. TASOR also interacts with the RNA exosome and with RNA Polymerase II predominantly in its elongating state, and facilitates the association of RNA degradation proteins with RNA Pol II at transcriptional centers.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, HIV LTR reporter assay, RNA Pol II co-IP, immunofluorescence at transcriptional centers\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast 2-hybrid plus co-IP and functional reporter assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35013187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TASOR is phosphorylated at T819 by a Cyclin/CDK1 complex, especially in cells arrested in early mitosis. However, this phosphorylation does not correlate with TASOR-mediated HIV-1 silencing, as T819A and T819E TASOR mutants repress HIV-1 LTR-driven expression similarly to wild-type TASOR.\",\n      \"method\": \"Phospho-specific antibody, nocodazole/etoposide cell cycle arrest, CDK1 inhibitor, TASOR point mutant overexpression in HIV-1 latency model\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — phospho-antibody detection plus functional mutant assay, but single lab and limited mechanistic follow-up on the phosphorylation's positive role\",\n      \"pmids\": [\"36309692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TASOR's DUF3715 domain adopts a pseudo-PARP (RDTS) structure with extensive structural homology to TEX15's DUF3715 domain. The DUF3715 domain from divergent TEX15 sequences can functionally substitute the DUF3715 domain of TASOR and mediate transposon silencing, establishing a conserved functional role for this domain in RNA-directed transposon silencing.\",\n      \"method\": \"Structural homology analysis, functional domain-swap experiments, transposon silencing reporter assay\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — structural analysis combined with functional domain-swap experiments, single lab\",\n      \"pmids\": [\"37433650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The HUSH complex (including TASOR) interacts with the transcription termination factor WDR82 and accumulates at sites of high RNAPII occupancy including long exons and transcription termination sites in a WDR82- and CPSF-dependent manner, demonstrating co-transcriptional chromatin targeting for genome surveillance.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, genetic epistasis with WDR82/CPSF knockouts, genomic rearrangement at Sox2 locus\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, ChIP-seq, epistatic knockouts, and natural genomic rearrangement experiment, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"37164018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HUSH complex (MPP8 and TASOR subunits) interacts with the leading-strand DNA polymerase Pol ε and contributes to asymmetric H3K9me3 distribution at replication forks (preferentially onto leading strands at LINE-1 elements). TASOR mutants with reduced Pol ε interaction show compromised H3K9me3 asymmetry and increased LINE expression.\",\n      \"method\": \"Co-immunoprecipitation, H3K9me3 strand-specific ChIP, TASOR interaction mutants, POLE3/POLE4 and MPP8/TASOR knockouts\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with Pol ε, strand-specific ChIP, multiple loss-of-function models, and interaction-defective TASOR mutants, multiple orthogonal methods in one study\",\n      \"pmids\": [\"37938774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AlphaFold3 modeling of the MPP8-TASOR complex predicts that a SPOC domain and a domain with a novel fold in TASOR form extended interaction interfaces with the MPP8 C-terminal domain (ankyrin repeats + PINIT-like domain). Point mutations at these predicted interfaces resulted in loss of HUSH-dependent transcriptional repression, validating the structural model.\",\n      \"method\": \"X-ray crystallography (MPP8 CTD), AlphaFold3 structural modeling, point mutagenesis, cell-based transcriptional repression reporter assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of MPP8 CTD with AlphaFold3 modeling and mutagenesis validation, single lab\",\n      \"pmids\": [\"39638237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TASOR loss in naive pluripotent stem cells triggers replication stress, disrupts H3K9me3 heterochromatin, and impairs silencing of LINE-1 transposable elements. Unscheduled L1 expression upon TASOR loss activates an innate immune response (MAVS pathway) leading to cell death specifically in cells exiting naive pluripotency; this is rescued by caspase inhibition or MAVS deletion.\",\n      \"method\": \"CRISPR knockout, H3K9me3 ChIP, LINE-1 expression analysis, caspase inhibitor treatment, MAVS genetic deletion, pluripotency transition assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockouts with multiple functional readouts and epistatic rescue, single lab\",\n      \"pmids\": [\"39453814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HuSH (HUSH) complex centered on TASOR and a second paralogous HuSH2 complex centered on TASOR2 localize to distinct, non-overlapping genomic loci; HUSH/TASOR represses LINE-1 retrotransposons. MPP8 interaction with TASOR is disrupted by specific amino acid substitutions guided by in silico structural predictions, and the relative quantities of HuSH complexes regulate LINE-1 activity.\",\n      \"method\": \"ChIP-seq, in silico protein structure prediction, mutagenesis of MPP8-TASOR interface, LINE-1 reporter assay, CRISPR knockout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, structural modeling with experimental mutagenesis validation, functional reporter assay, single lab\",\n      \"pmids\": [\"39489739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Vpx-mediated degradation of TASOR leads to increased LINE-1 activity, which in turn activates innate immune sensing; ISG induction by Vpx-mediated TASOR degradation relies on both RNA sensing (MAVS signaling) and DNA sensing (cGAS/STING signaling).\",\n      \"method\": \"Vpx mutant analysis, transcriptomic analysis, TASOR degradation experiments, MAVS and cGAS/STING pathway inhibition\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Vpx mutant dissection with pathway-specific inhibitors, single lab, multiple readouts\",\n      \"pmids\": [\"42190982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Periphilin is the major RNA-binding component of the HUSH complex; its N-terminal domain is essential for both RNA binding and HUSH function. Artificial tethering of Periphilin to a HUSH-insensitive nascent transcript enables HUSH-dependent silencing of that transcript, establishing that Periphilin's RNA binding initiates HUSH silencing. Periphilin's RNA binding is independent of its interaction with TASOR or MPP8.\",\n      \"method\": \"Unbiased RNA-binding assay, domain truncation analysis, tethering reporter assay, mutagenesis of Periphilin NTD\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased RNA-binding identification, domain mapping, and tethering functional assay, single lab; directly informs TASOR complex mechanism\",\n      \"pmids\": [\"39658355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In mouse embryonic stem cells, deficiency of both MPP8 and TASOR (double mutant) locks cells in pluripotent state even upon differentiation stimuli, and decreases expression of adhesion-related genes (keratins 18 and 19); ectopic co-expression of keratins 18 and 19 rescues the exit-from-pluripotency defect.\",\n      \"method\": \"CRISPR-based knockout, pluripotency exit assay, gene expression analysis, ectopic expression rescue\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic double knockout with functional rescue by downstream effectors, single lab\",\n      \"pmids\": [\"41291012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRC1.6 components L3MBTL2 and MGA contribute to HUSH complex-mediated provirus silencing in a promoter-specific manner. PRC1.6 and HUSH complexes co-localize on chromatin primarily at active promoters, and PRC1.6 binding at a subset of HUSH-silenced genes is dependent on core HUSH component MPP8.\",\n      \"method\": \"Proximity labeling (C-BERST/dCas9-APEX2), forward genetic screen, ChIP-seq co-localization, MPP8-dependent PRC1.6 binding analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling screen with ChIP-seq validation and forward genetic screen confirmation, preprint, single lab\",\n      \"pmids\": [\"39026796\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TASOR is the central scaffolding subunit of the HUSH (human silencing hub) complex, which it assembles with MPP8 and Periphilin via a catalytically-inactive pseudo-PARP (RDTS/DUF3715) domain; the complex recruits SETDB1 to deposit H3K9me3 at LINE-1 retrotransposons, integrated retroviruses, and repetitive transgenes, with RNA-mediated targeting initiated by Periphilin's nascent-RNA binding, co-transcriptional surveillance coupled to RNAPII termination machinery (WDR82/CPSF), asymmetric H3K9me3 inheritance facilitated by interaction with leading-strand polymerase Pol ε during replication, and post-transcriptional repression involving the CNOT1 RNA deadenylase complex and RNA exosome; HIV-2/SIV Vpx counteracts TASOR by forming a ternary complex with DCAF1 to drive proteasomal degradation of TASOR, whose loss de-represses LINE-1s and activates innate immune sensing via MAVS and cGAS/STING.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TASOR is the central scaffolding subunit of the HUSH (human silencing hub) complex, which it assembles with MPP8 and Periphilin to deposit H3K9me3 heterochromatin and transcriptionally silence retroviruses, repetitive transgenes, and evolutionarily young, full-length LINE-1 retrotransposons residing in euchromatin [#0, #1, #4]. TASOR organizes the complex through defined interaction interfaces—an N-terminal catalytically-inactive pseudo-PARP (DUF3715/RDTS) domain required for targeted H3K9me3 deposition and silencing, a SPOC and novel-fold module engaging the MPP8 C-terminal domain, and a minimal core that binds a Periphilin homodimer—and through these contacts recruits the methyltransferase SETDB1 to establish and maintain silencing [#4, #5, #9, #12, #14]. Targeting is RNA-directed and co-transcriptional: Periphilin's N-terminal domain binds nascent transcripts to initiate silencing [#16], while TASOR couples the complex to elongating RNA Polymerase II and to RNA-degradation machinery including the CNOT1/CCR4-NOT deadenylase complex and the RNA exosome, and accumulates at sites of high RNAPII occupancy and transcription termination through the WDR82/CPSF termination machinery [#7, #10]. During replication, HUSH interacts with leading-strand polymerase Pol ε to propagate asymmetric H3K9me3 onto leading strands at LINE-1 elements [#11]. Loss of TASOR de-represses LINE-1s, triggering replication stress and activating innate immune sensing via MAVS and cGAS/STING [#13, #15]. The HIV-2/SIV accessory protein Vpx antagonizes this pathway by stabilizing a ternary complex between TASOR's N-terminal PARP-like domain, DCAF1, and the CUL4 E3 ligase to drive proteasomal degradation of TASOR, reactivating latent proviruses [#2, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that TASOR is a core subunit of a previously unknown silencing complex that maintains H3K9me3 heterochromatin, answering how certain integrated retroviruses and genomic loci are kept transcriptionally silent.\",\n      \"evidence\": \"Forward genetic screen in haploid KBM7 cells with ChIP for H3K9me3\",\n      \"pmids\": [\"26022416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how HUSH is targeted to specific loci\", \"Did not assign TASOR a distinct molecular function within the complex\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified the principal endogenous targets of HUSH as young, full-length LINE-1 elements in permissive euchromatin, explaining the complex's role in genome surveillance and its impact on host gene expression.\",\n      \"evidence\": \"Genome-wide CRISPR screen and ChIP-seq in two human cell lines\",\n      \"pmids\": [\"29211708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how young L1 elements are recognized\", \"Mechanism of co-transcriptional targeting unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed that HIV-2/SIV Vpx counteracts HUSH by inducing proteasomal degradation of TASOR via DCAF1-CUL4, linking the complex to retroviral latency and host antiviral defense.\",\n      \"evidence\": \"Proteomic screen, co-IP, proteasome inhibitor rescue, and HIV latency reactivation assays (two concurrent papers)\",\n      \"pmids\": [\"29891865\", \"30297740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the TASOR domains engaged by Vpx/DCAF1\", \"Did not address whether degradation is selective for specific HUSH functions\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed HUSH/TASOR is recruited by NP220 to silence unintegrated retroviral DNA together with SETDB1 and HDACs, broadening the range of foreign DNA the complex restricts.\",\n      \"evidence\": \"Genome-wide CRISPR screen, ChIP, and knockout validation\",\n      \"pmids\": [\"30487602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define TASOR's direct contribution versus other recruited factors\", \"Generality of NP220-dependent recruitment unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined TASOR as the central scaffold whose pseudo-PARP domain is required for H3K9me3 deposition independent of complex assembly, and resolved the Periphilin-TASOR core interface, providing the architectural basis of HUSH.\",\n      \"evidence\": \"Biochemical reconstitution, domain mutagenesis, ChIP-seq, reporter assays, and X-ray crystallography of the Periphilin-TASOR core\",\n      \"pmids\": [\"33009411\", \"32976585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the catalytic or binding function of the pseudo-PARP domain\", \"Did not resolve the TASOR-MPP8 interface\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped TASOR's N-terminal PARP-like domain as the DCAF1-binding region and showed TASOR-DCAF1 association is constitutive but Vpx-stabilized into a degradative ternary complex, clarifying the molecular logic of Vpx antagonism.\",\n      \"evidence\": \"Co-IP with domain and Vpx point mutants plus HIV reporter assay\",\n      \"pmids\": [\"34699574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Physiological role of basal TASOR-DCAF1 interaction unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected TASOR to post-transcriptional repression by demonstrating interactions with CNOT1, the RNA exosome, and elongating RNA Pol II, indicating HUSH couples chromatin silencing to RNA degradation at transcription centers.\",\n      \"evidence\": \"Yeast two-hybrid screen, co-IP, RNA Pol II co-IP, and HIV LTR reporter assays\",\n      \"pmids\": [\"35013187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct versus indirect nature of RNA-degradation coupling not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified CDK1-mediated phosphorylation of TASOR at T819 in mitosis, but showed it is dispensable for HIV-1 silencing, indicating this modification is not required for the repressive function tested.\",\n      \"evidence\": \"Phospho-specific antibody, cell cycle arrest, CDK1 inhibition, and T819 point mutant assays in an HIV-1 latency model\",\n      \"pmids\": [\"36309692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Positive functional role of T819 phosphorylation, if any, undefined\", \"Single lab and limited mechanistic follow-up\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established the DUF3715/pseudo-PARP domain as a conserved RNA-directed silencing module by showing TEX15's homologous domain functionally substitutes in TASOR, deepening understanding of how this domain enables transposon silencing.\",\n      \"evidence\": \"Structural homology analysis and domain-swap transposon silencing assays\",\n      \"pmids\": [\"37433650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Biochemical activity contributed by the domain remains undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed HUSH co-transcriptional targeting requires the termination factor WDR82 and CPSF, with the complex accumulating at high-RNAPII-occupancy regions, explaining how silencing is directed to actively transcribed repetitive loci.\",\n      \"evidence\": \"Reciprocal co-IP, ChIP-seq, epistatic WDR82/CPSF knockouts, and a Sox2 genomic rearrangement experiment\",\n      \"pmids\": [\"37164018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the RNA signal is converted to chromatin recruitment unresolved\", \"TASOR-specific role within this targeting not isolated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated HUSH interacts with leading-strand polymerase Pol ε to propagate asymmetric H3K9me3 at replication forks, providing a mechanism for heritable maintenance of LINE-1 silencing through replication.\",\n      \"evidence\": \"Co-IP with Pol ε, strand-specific H3K9me3 ChIP, POLE3/POLE4 and MPP8/TASOR knockouts, and interaction-defective TASOR mutants\",\n      \"pmids\": [\"37938774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TASOR-Pol ε interaction not defined\", \"Lagging-strand restoration mechanism unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the TASOR-MPP8 interface using crystallography and AlphaFold3 modeling validated by mutagenesis, completing the structural map of HUSH subunit contacts required for repression.\",\n      \"evidence\": \"X-ray crystallography of MPP8 CTD, AlphaFold3 modeling, point mutagenesis, and reporter assays\",\n      \"pmids\": [\"39638237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Model-derived interfaces partly predictive rather than experimentally resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a paralogous HuSH2 complex centered on TASOR2 occupying distinct genomic loci, with TASOR-HUSH dedicated to LINE-1 repression and HUSH stoichiometry tuning L1 activity.\",\n      \"evidence\": \"ChIP-seq, in silico structural prediction, MPP8-TASOR interface mutagenesis, and LINE-1 reporter assays\",\n      \"pmids\": [\"39489739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional division of labor between HUSH and HuSH2 incompletely defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected TASOR loss to physiological consequences by showing de-repressed LINE-1 triggers replication stress and MAVS-dependent innate immune death during exit from naive pluripotency.\",\n      \"evidence\": \"CRISPR knockout, H3K9me3 ChIP, L1 expression analysis, caspase inhibition, and MAVS deletion in stem cells\",\n      \"pmids\": [\"39453814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether replication stress is a direct or downstream consequence of L1 activation unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked HUSH to PRC1.6 components L3MBTL2 and MGA at active promoters, with promoter-specific MPP8-dependent PRC1.6 recruitment, expanding the repressive cofactor network.\",\n      \"evidence\": \"Proximity labeling (dCas9-APEX2), forward genetic screen, and ChIP-seq co-localization (preprint)\",\n      \"pmids\": [\"39026796\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Direct TASOR contribution to PRC1.6 recruitment not isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that Vpx-driven TASOR degradation activates both RNA (MAVS) and DNA (cGAS/STING) innate sensing pathways via increased LINE-1 activity, integrating HUSH antagonism with antiviral signaling.\",\n      \"evidence\": \"Vpx mutant dissection, transcriptomics, and MAVS and cGAS/STING pathway inhibition\",\n      \"pmids\": [\"42190982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Relative contributions of RNA versus DNA sensing not quantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established Periphilin as the RNA-binding initiator of HUSH silencing, showing its N-terminal domain binds nascent transcripts and that tethering Periphilin suffices to silence a HUSH-insensitive transcript, defining the upstream targeting trigger.\",\n      \"evidence\": \"Unbiased RNA-binding assay, domain truncation, Periphilin NTD mutagenesis, and tethering reporter assay\",\n      \"pmids\": [\"39658355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How Periphilin RNA recognition is converted to TASOR/MPP8-dependent chromatin modification unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed combined MPP8/TASOR loss locks mouse ES cells in pluripotency by suppressing keratin 18/19 adhesion genes, with keratin re-expression rescuing differentiation, linking HUSH to a developmental gene-regulatory output.\",\n      \"evidence\": \"CRISPR double knockout, pluripotency exit assay, gene expression analysis, and ectopic keratin rescue\",\n      \"pmids\": [\"41291012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanistic link between HUSH silencing and keratin regulation undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical activity contributed by TASOR's pseudo-PARP domain and how nascent-RNA recognition by Periphilin is mechanistically transduced into TASOR-directed SETDB1 recruitment and H3K9me3 deposition remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No catalytic activity assigned to the pseudo-PARP domain\", \"Step-wise coupling from RNA binding to chromatin modification not reconstituted\", \"Full-complex structure with SETDB1 not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 5, 12]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 1, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 6, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 15]}\n    ],\n    \"complexes\": [\"HUSH complex\"],\n    \"partners\": [\"MPP8\", \"PPHLN1\", \"SETDB1\", \"DCAF1\", \"CNOT1\", \"WDR82\", \"POLE\", \"RNA Pol II\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}