Affinage

CHTOP

Chromatin target of PRMT1 protein · UniProt Q9Y3Y2

Length
248 aa
Mass
26.4 kDa
Annotated
2026-06-09
13 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHTOP is a vertebrate arginine-rich nuclear and nucleolar protein that couples mRNA export to arginine-methylation-dependent control of gene expression (PMID:23299939, PMID:19254951). As a dynamic component of the TREX complex, CHTOP activates the ATPase and RNA helicase activities of Uap56 and is loaded with Alyref onto mRNA, then binds the NTF2-like domain of Nxf1 in a manner requiring its own arginine methylation; its Nxf1 and Uap56 contacts are mutually exclusive with Thoc5 and Alyref respectively, so that Uap56 ATPase activity and CHTOP modification drive remodelling of TREX during export, and co-depletion of CHTOP and Alyref blocks bulk mRNA export (PMID:23299939). CHTOP binds competitively to PRMT1 and PRMT5, directing either asymmetric or symmetric arginine methylation, and this methylation state governs its functional partnerships (PMID:29683372). On chromatin, CHTOP binds 5-hydroxymethylcytosine and recruits the PRMT1-containing methylosome to promote H4R3 methylation and transcriptional activation of growth-promoting genes, a role required for glioblastoma cell tumorigenicity (PMID:25284789). PRMT1-dependent methylation of CHTOP is also the trigger for assembly of the 5FMC complex (Pelp1, Senp3, Wdr18, Tex10, Las1L), which alters the sumoylation and transactivation of the transcription factor Zbp-89 (PMID:22872859), and is required for the post-transcriptional processing of nucleoplasm- and chromatin-retained detained introns (PMID:34984976). CHTOP abundance is autoregulated through intron retention coupled to nonsense-mediated mRNA decay (PMID:29683372), and the protein is appropriated by KSHV ORF57 to support viral mRNA export (PMID:27189710).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2009 Medium

    Established the basic cell biology of CHTOP: where it resides, that it contacts RNA, and that its level tracks proliferative state, framing it as a regulated nuclear/nucleolar RNA-associated factor.

    Evidence Subcellular fractionation, immunofluorescence, N-terminal truncation mutants, and cell-cycle flow cytometry in cultured cells

    PMID:19254951

    Open questions at the time
    • No molecular partners or biochemical activity identified
    • Mechanism linking CHTOP level to G2/M and cell death not defined
    • RNA-binding specificity unresolved
  2. 2012 High

    Showed that arginine methylation of CHTOP is the switch that nucleates a defined nuclear complex, connecting a post-translational mark to transcriptional control via desumoylation.

    Evidence Biotinylation-proteomics, mass spectrometry, Co-IP, and sumoylation/transactivation assays defining the 5FMC complex and its effect on Zbp-89

    PMID:22872859

    Open questions at the time
    • Generality of 5FMC targets beyond Zbp-89 unknown
    • Structural basis of methyl-CHTOP recognition by Pelp1 not resolved
    • Direct desumoylation of Zbp-89 by Senp3 within the complex not reconstituted
  3. 2013 High

    Identified CHTOP as a core, dynamic TREX subunit and defined the biochemical logic of export-complex remodelling, explaining how mRNA is handed to the Nxf1 export receptor.

    Evidence Reciprocal Co-IP, Uap56 ATPase/helicase assays, RNAi co-knockdown with mRNA export readout in human cells

    PMID:23299939

    Open questions at the time
    • Identity of the methyltransferase acting on CHTOP within TREX not pinned in this study
    • Stoichiometry and order of Alyref/CHTOP exchange on individual transcripts unknown
    • Structure of the CHTOP-Nxf1 interface not solved
  4. 2014 High

    Connected CHTOP to chromatin directly by showing it reads 5hmC and writes an activating histone mark through the methylosome, establishing a co-activator role with oncogenic consequences.

    Evidence ChIP, Co-IP, in vitro methylation assays, and RNAi with transcriptional and tumorigenicity readouts in glioblastoma cells

    PMID:25284789

    Open questions at the time
    • Domain mediating 5hmC recognition not mapped
    • Whether export and chromatin functions are physically separable not addressed
    • Breadth of CHTOP-methylosome target genes beyond the named oncogenes unknown
  5. 2018 Medium

    Revealed that CHTOP partitions between two antagonistic PRMTs and that its own abundance is feedback-controlled, positioning it as a tunable hub for methylation-dependent outputs.

    Evidence Competitive Co-IP binding assays and intron-retention/NMD analysis with NMD inhibitors

    PMID:29683372

    Open questions at the time
    • Cellular signals that bias PRMT1 versus PRMT5 binding not identified
    • Quantitative contribution of NMD autoregulation to steady-state CHTOP unknown
    • Methods compressed in abstract; competitive binding not independently confirmed
  6. 2022 High

    Demonstrated that CHTOP arginine methylation directly governs post-transcriptional processing of detained introns, linking its modification state to splicing outcomes downstream of transcription.

    Evidence Type I PRMT inhibition, methylarginine-site mutagenesis, SKaTER-seq, actinomycin D chase, and chromatin-fraction proteomics in human cells

    PMID:34984976

    Open questions at the time
    • Mechanism by which methyl-CHTOP promotes intron removal not defined
    • Splicing factors recruited by CHTOP for detained introns unidentified
    • Overlap with TREX export function on the same transcripts unresolved
  7. 2016 Medium

    Showed a viral pathogen co-opts CHTOP, establishing that its TREX-based export activity is required for processing and export of viral mRNAs.

    Evidence Co-IP and siRNA depletion with viral mRNA processing assays for KSHV ORF57

    PMID:27189710

    Open questions at the time
    • Direct versus TREX-mediated CHTOP-ORF57 contact not distinguished
    • Single Co-IP/depletion study
    • Selectivity for viral over host transcripts not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CHTOP's separate functions — TREX-mediated export, 5hmC/histone co-activation, 5FMC desumoylation, and intron-detention processing — are coordinated, and what determines its choice of PRMT and downstream complex on a given transcript or locus, remains unresolved.
  • No structural model of CHTOP or its methyl-dependent interfaces
  • No genome-wide integration of its chromatin versus RNA-export roles
  • Signals controlling PRMT1/PRMT5 partitioning unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0140110 transcription regulator activity 2 GO:0060090 molecular adaptor activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005694 chromosome 2 GO:0005634 nucleus 1 GO:0005654 nucleoplasm 1 GO:0005730 nucleolus 1
Pathway
R-HSA-1643685 Disease 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-4839726 Chromatin organization 1
Partners
ALYREFNXF1PELP1PRMT1PRMT5SENP3UAP56ZNF148
Complex memberships
5FMC complexTREX complexmethylosome

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Chtop is a novel component of the TREX mRNA export complex. Chtop activates the ATPase and RNA helicase activities of Uap56 (similar to Alyref). Uap56 recruits both Alyref and Chtop onto mRNA. Chtop binds to the NTF2-like domain of Nxf1 in a manner requiring arginine methylation of Chtop, and this interaction is mutually exclusive with Thoc5 binding. Chtop binds Uap56 in a mutually exclusive manner with Alyref. Co-knockdown of Alyref and Chtop results in a potent mRNA export block. Together, these interactions indicate TREX and Nxf1 undergo dynamic remodelling driven by Uap56 ATPase activity and Chtop post-translational modifications. Co-immunoprecipitation, RNAi knockdown, ATPase/helicase activity assays, mRNA export assays The EMBO journal High 23299939
2012 Chtop interacts with a nuclear complex called Five Friends of Methylated Chtop (5FMC), which can only be recruited when Chtop is arginine-methylated by Prmt1. 5FMC consists of Pelp1 (core scaffold), Senp3 (SUMO-specific protease), Wdr18, Tex10, and Las1L. Recruitment of 5FMC to the zinc-finger transcription factor Zbp-89 affects its sumoylation status and transactivation potential, providing a mechanistic link between arginine methylation and desumoylation in transcriptional control. Biotinylation-proteomics (BioID-like approach), mass spectrometry, co-immunoprecipitation, sumoylation/transactivation assays Molecular & cellular proteomics : MCP High 22872859
2014 CHTOP binds to 5-hydroxymethylcytosine (5hmC) on chromatin and is associated with the arginine methyltransferase methylosome complex. This CHTOP-methylosome complex promotes PRMT1-mediated methylation of arginine 3 of histone H4 (H4R3) at genes involved in glioblastomagenesis (EGFR, AKT3, CDK6, CCND2, BRAF), thereby activating their transcription. CHTOP and PRMT1 are both required for expression of these genes, and CHTOP is required for glioblastoma cell tumorigenicity. Chromatin immunoprecipitation, co-immunoprecipitation, RNAi knockdown, in vitro methylation assay, gene expression analysis Cell reports High 25284789
2009 SRAG (CHTOP) localizes to the nucleus and nucleolus; nucleolar localization is regulated by the N-terminal domain. CHTOP can interact with RNA. Full-length CHTOP protein levels are highest in resting cells and reduced in proliferating cells, with reduction mapping to the G2/M phase. Overexpression of CHTOP reduces the percentage of cells in G2/M and increases cell death. Subcellular fractionation, immunofluorescence microscopy, N-terminal truncation mutants, cell cycle analysis (flow cytometry), overexpression studies The Journal of biological chemistry Medium 19254951
2022 Arginine methylation of CHTOP by Type I PRMTs regulates post-transcriptional intron detention. Mutagenesis of all methylarginine sites in CHTOP recapitulated the retained-intron splicing changes seen with Type I PRMT inhibition. CHTOP occupancy on chromatin-associated polyadenylated RNA is altered upon Type I PRMT inhibition. Retained introns are enriched in nucleoplasm and chromatin fractions, and CHTOP arginine methylation is required for their post-transcriptional processing. PRMT inhibition (pharmacological), targeted mutagenesis of methylarginine sites, SKaTER-seq (co-transcriptional splicing kinetics), actinomycin D transcription block, proteomic analysis of chromatin fractions, subcellular fractionation eLife High 34984976
2018 Chtop binds competitively to both PRMT1 and PRMT5, thereby promoting either asymmetric or symmetric methylation of arginine residues depending on which enzyme is bound. Cellular Chtop levels are autoregulated by a mechanism involving intron retention and nonsense-mediated mRNA decay (NMD). Competitive binding assays (Co-IP), intron retention and NMD analysis (RNA analysis with NMD inhibitors) RNA biology Medium 29683372
2016 KSHV ORF57 protein interacts with CHTOP (and CIP29) as components of the human TREX complex. Depletion of CHTOP affects ORF57-mediated viral mRNA processing, indicating CHTOP is recruited into an ORF57-mediated viral ribonucleoprotein particle (vRNP) and is functionally required for viral mRNA export. Co-immunoprecipitation, siRNA depletion, viral mRNA processing assays The Journal of general virology Medium 27189710

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 5-Hydroxymethylcytosine plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex. Cell reports 109 25284789
2013 Chtop is a component of the dynamic TREX mRNA export complex. The EMBO journal 98 23299939
2012 Five friends of methylated chromatin target of protein-arginine-methyltransferase[prmt]-1 (chtop), a complex linking arginine methylation to desumoylation. Molecular & cellular proteomics : MCP 49 22872859
2022 Type I and II PRMTs inversely regulate post-transcriptional intron detention through Sm and CHTOP methylation. eLife 33 34984976
2021 CircHIPK2 Contributes to DDP Resistance and Malignant Behaviors of DDP-Resistant Ovarian Cancer Cells Both in vitro and in vivo Through circHIPK2/miR-338-3p/CHTOP ceRNA Pathway. OncoTargets and therapy 22 34012271
2020 Circulating unmethylated CHTOP and INS DNA fragments provide evidence of possible islet cell death in youth with obesity and diabetes. Clinical epigenetics 21 32736653
2009 Identification of the small protein rich in arginine and glycine (SRAG): a newly identified nucleolar protein that can regulate cell proliferation. The Journal of biological chemistry 16 19254951
2018 Modulating the expression of Chtop, a versatile regulator of gene-specific transcription and mRNA export. RNA biology 14 29683372
2016 The small RNA SraG participates in PNPase homeostasis. RNA (New York, N.Y.) 13 27495318
2012 Small non-coding RNA SraG regulates the operon YPK_1206-1205 in Yersinia pseudotuberculosis. FEMS microbiology letters 13 22428705
2021 Srag Regulates Autophagy via Integrating into a Preexisting Autophagy Pathway in Testis. Molecular biology and evolution 10 32722765
2019 CHTOP in Chemoresistant Epithelial Ovarian Cancer: A Novel and Potential Therapeutic Target. Frontiers in oncology 10 31380263
2016 Interactions between KSHV ORF57 and the novel human TREX proteins, CHTOP and CIP29. The Journal of general virology 8 27189710

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