Affinage

THOC5

THO complex subunit 5 · UniProt Q13769

Length
683 aa
Mass
78.5 kDa
Annotated
2026-04-28
31 papers in source corpus 19 papers cited in narrative 19 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

THOC5 is a subunit of the THO/TREX complex that functions as a selective mRNA export adaptor, coupling transcription elongation, 3'-end processing, and nuclear export for a specific subset of mRNAs critical to hematopoietic stem cell maintenance, lineage commitment, and stress-responsive gene expression. THOC5 binds the NTF2-like domain of the export receptor NXF1/Tap at a site distinct from Aly, enabling simultaneous adaptor engagement, and directly associates with 3'-end processing factors CFIm68 and CPSF100 to control polyadenylation site choice — its depletion causes widespread alternative cleavage and failure to release select transcripts from chromatin (PMID:19165146, PMID:23685434, PMID:25274738). THOC5 also modulates transcription elongation rate, forming a chromatin-associated complex with CDK12, DDX5, and DDX17 that promotes CDK12 recruitment to R-loops in a THOC6-dependent manner (PMID:36590164). Multiple signaling kinases regulate THOC5 function: PKC phosphorylation at S5/S6 controls its nuclear–cytoplasmic shuttling, ATM phosphorylation at S307/S312/S314 suppresses its mRNA-binding capacity upon DNA damage, and Src-mediated Y225 phosphorylation modulates RNA binding in hematopoietic cells (PMID:15221008, PMID:21937706, PMID:23032722).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1999 High

    The initial identification of THOC5 (as FMIP) established it as a cytokine receptor-interacting protein whose expression level influences myeloid lineage commitment, raising the question of how a nuclear/cytoplasmic protein connects growth factor signaling to cell fate.

    Evidence Co-IP and GST pulldown with c-Fms cytoplasmic domain; overexpression in FDC-P1Mac11 bipotential cells shifted differentiation from macrophage to granulocyte

    PMID:10597251

    Open questions at the time
    • Mechanism linking Fms-induced tyrosine phosphorylation to differentiation outcome not defined
    • Endogenous target mRNAs unknown at this stage
  2. 2004 High

    Demonstrating that PKC phosphorylation at S5/S6 governs THOC5 nuclear-cytoplasmic shuttling established a signal-regulated localization mechanism and linked nucleo-cytoplasmic distribution to differentiation function.

    Evidence Phosphomimetic and phospho-null mutants at S5/S6 combined with subcellular fractionation, immunofluorescence, and macrophage differentiation readout

    PMID:15221008

    Open questions at the time
    • Whether shuttling directly controls mRNA export was not tested
    • Upstream signals activating PKC in this context not defined
  3. 2006 Medium

    Showing that THOC5 overexpression blocks C/EBPα mRNA polyadenylation and that THOC5 co-precipitates with THOC1 first linked THOC5 to the THO complex and to mRNA 3'-end processing rather than simple transport.

    Evidence Northern blot distinguishing pre-mRNA from mRNA in C2C12 adipocyte/myocyte differentiation; Co-IP with THOC1

    PMID:16909111

    Open questions at the time
    • Mechanism of polyadenylation inhibition not resolved
    • Whether THOC5 acts through CFIm or CPSF not yet known
  4. 2009 High

    Mapping the THOC5–NXF1/Tap interaction to a distinct surface on the NTF2-like domain, non-overlapping with Aly, established THOC5 as a bona fide mRNA export adaptor with selective (not bulk) export function.

    Evidence In vitro binding, Co-IP, RNA-binding assay, siRNA knockdown with HSP70 mRNA export readout

    PMID:19165146

    Open questions at the time
    • Determinants specifying which mRNAs require THOC5 for export unknown
    • Structural basis of simultaneous THOC5–Aly binding to Tap unresolved
  5. 2010 High

    In vivo conditional knockout proved THOC5 is essential for hematopoietic stem/progenitor cell maintenance, demonstrating that its selective mRNA export function has non-redundant physiological consequences in rapidly dividing progenitors.

    Evidence Interferon-inducible conditional KO mice with bone marrow rescue, flow cytometry, apoptosis assay

    PMID:20051105

    Open questions at the time
    • Which specific mRNA targets are responsible for the HSC phenotype not identified
    • Whether THOC5 loss causes R-loop-mediated genomic instability in HSCs not tested
  6. 2011 High

    Identification of specific THOC5-dependent mRNA substrates (HoxB3, CBX2) and demonstration that ATM phosphorylation at S307/S312/S314 suppresses THOC5 mRNA binding after DNA damage established a stress-responsive regulatory axis controlling selective mRNA export.

    Evidence Conditional KO MEFs with nuclear/cytoplasmic fractionation and RNA-IP (mRNA substrates); mutagenesis at S307/312/314, ATM inhibitor KU55933, RNA-IP (phosphoregulation)

    PMID:21525145 PMID:21937706

    Open questions at the time
    • How ATM-dependent phosphorylation mechanistically alters RNA binding when the phosphosites are dispensable for RNA binding is unclear
    • Overlap between ATM-regulated and HSC-essential THOC5 targets not defined
  7. 2012 High

    Showing that Src phosphorylates THOC5 at Y225 to regulate mRNA binding, with elevated Y225 phosphorylation in CML stem cells sensitive to tyrosine kinase inhibitors, linked THOC5 phosphoregulation to leukemia biology.

    Evidence Y225 mutagenesis, RNA-IP, kinase/phosphatase co-expression, CML patient samples, dasatinib/imatinib sensitivity

    PMID:23032722

    Open questions at the time
    • Whether Y225 phosphorylation alters substrate selectivity or global mRNA binding not resolved
    • Causal role in CML pathogenesis not demonstrated by loss-of-function in vivo
  8. 2013 High

    Discovery that THOC5 directly interacts with CFIm68 and CPSF100, and that its depletion phenocopies CFIm68 loss in polyadenylation site choice, established THOC5 as a co-transcriptional coordinator coupling mRNA export to 3'-end processing.

    Evidence Co-IP, ChIP-Seq for CFIm68 occupancy upon THOC5 depletion, microarray, interactome analysis with CPSF100, conditional KO

    PMID:23685434 PMID:25274738

    Open questions at the time
    • Whether THOC5 directly bridges RNA polymerase II and 3'-processing machinery or acts indirectly through chromatin state
    • Structural basis of THOC5–CFIm68 and THOC5–CPSF100 interactions not determined
  9. 2013 High

    Identification of tissue-specific THOC5-dependent mRNA targets in intestinal epithelium (Sox9, Ascl2) and during macrophage differentiation (Ets1) broadened THOC5's role to multiple stem/progenitor cell compartments and showed its chromatin recruitment at target loci.

    Evidence Tamoxifen-inducible conditional KO mice, RNA-IP, ChIP, intestinal and macrophage phenotype analysis

    PMID:24157873 PMID:24267292

    Open questions at the time
    • Cis-elements in target mRNAs recognized by THOC5 not identified
    • How THOC5 is recruited to specific chromatin loci not mechanistically resolved
  10. 2022 High

    Demonstration that THOC5 depletion reduces transcription elongation rates and that chromatin-bound THOC5 forms a complex with CDK12, DDX5, and DDX17 to resolve R-loops unified THOC5's roles in elongation, processing, and genome integrity.

    Evidence Elongation rate measurements in vivo, Pol II ChIP-seq, Co-IP of CDK12/DDX5/DDX17, R-loop analysis

    PMID:36590164

    Open questions at the time
    • Whether THOC5 directly stimulates CDK12 kinase activity or merely facilitates its chromatin loading
    • Relative contributions of elongation rate changes versus 3'-processing defects to gene expression changes not separated
  11. 2024 Medium

    Establishing that SF3B1 K700E cancer mutation weakens SF3B1–THOC5 interaction and that THOC5 overexpression rescues the resulting mRNA export defect connected spliceosome integrity to THOC5-dependent export.

    Evidence Co-IP, RNA-IP, nuclear/cytoplasmic fractionation, THOC5 overexpression rescue in SF3B1 K700E cells

    PMID:39259498

    Open questions at the time
    • Whether SF3B1–THOC5 interaction is direct or bridged by other TREX components not determined
    • Which mRNA features specify dependence on SF3B1-mediated THOC5 recruitment unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the cis-acting RNA elements that confer THOC5 selectivity, the structural basis for simultaneous engagement of NXF1, 3'-processing factors, and CDK12, and whether THOC5 phosphorylation switches alter substrate specificity or global RNA-binding capacity.
  • No RNA motif or structural element specifying THOC5-dependent export has been identified
  • No high-resolution structure of THOC5 in complex with NXF1 or processing factors exists
  • How multiple phosphorylation inputs (PKC, ATM, Src) are integrated on a single THOC5 molecule in vivo is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 3 GO:0005829 cytosol 2
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-1266738 Developmental Biology 4 R-HSA-9609507 Protein localization 4 R-HSA-73894 DNA Repair 1 R-HSA-74160 Gene expression (Transcription) 1
Partners
CDK12CFIM68CPSF100NXF1SF3B1THOC1THOC6THOC7
Complex memberships
THO/TREX complex

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 THOC5 binds to a distinct surface on the middle (Ntf2-like) domain of Tap (NXF1), at a non-overlapping site from adaptor Aly, allowing THOC5 and Aly to simultaneously bind Tap-p15. THOC5 exhibits in vitro RNA-binding activity and is required for nuclear export of HSP70 mRNA but not bulk mRNA export. Co-immunoprecipitation, in vitro binding assay, RNA-binding assay, siRNA knockdown with mRNA export readout The EMBO journal High 19165146
1999 THOC5 (FMIP) binds transiently via its N-terminal 144 residues to the cytoplasmic domain of activated c-Fms (M-CSF receptor) and is rapidly tyrosine-phosphorylated upon binding, which reduces its ability to associate with Fms. Overexpression of THOC5 redirects bipotential myeloid progenitors from macrophage to granulocyte differentiation. Co-immunoprecipitation, GST-pulldown with recombinant Fms fusion proteins, overexpression in FDC-P1Mac11 cells with differentiation readout Oncogene High 10597251
2004 THOC5 (FMIP) is phosphorylated by protein kinase C (PKC) on serines 5 and 6 adjacent to its nuclear localization signal (NLS). PKC-mediated phosphorylation causes translocation of THOC5 from the nucleus to the cytosol; phosphomimetic (SS5,6EE) mutation promotes cytoplasmic localization and enhanced M-CSF-mediated macrophage differentiation, while the non-phosphorylatable (SS5,6AA) mutant remains nuclear even in the presence of active PKCα. Site-directed mutagenesis, subcellular fractionation, immunofluorescence, overexpression of phosphomimetic/phospho-null mutants Oncogene High 15221008
2006 THOC5 (FMIP) controls adipocyte versus muscle lineage commitment in C2C12 cells by regulating C/EBPα mRNA processing/export; ectopic FMIP expression prevents polyadenylation of C/EBPalpha mRNA (pre-mRNA accumulates), and THOC1 co-precipitates with FMIP. siRNA knockdown, ectopic overexpression, Northern blot/RT-PCR for pre-mRNA vs mRNA distinction, co-immunoprecipitation with THOC1 Oncogene Medium 16909111
2008 THOC7 nuclear localization depends on direct interaction with THOC5 (FMIP): THOC7 (residues 50-137) binds to the N-terminal portion (1-199) of THOC5, and THOC5 acts as a nuclear import chaperone for THOC7. Co-immunoprecipitation, deletion mapping, colocalization microscopy, overexpression of FMIP binding-site mutant of THOC7 FEBS letters Medium 19059247
2008 THOC5 forms a complex with C/EBPβ and its elevated expression mimics M-CSF-mediated monocyte maturation, enhancing C/EBPβ, C/EBPα, PU.1, and GAB2 protein levels and increasing PtdInsP3 levels; inhibition of PtdInsP3 abrogates THOC5-induced C/EBPβ elevation. Co-immunoprecipitation, ectopic overexpression, inhibitor treatment, flow cytometry for differentiation markers Cellular signalling Medium 19015024
2010 THOC5 is essential for maintenance of hematopoietic primitive/stem cells in vivo; conditional THOC5 knockout causes rapid loss of committed myeloid progenitors and long-term reconstituting cells from bone marrow with apoptosis, and depletion of THOC5 causes downregulation of its direct interacting partner THOC1. Interferon-inducible conditional knockout mice, bone marrow rescue experiment, flow cytometry, apoptosis assay BMC biology High 20051105
2011 THOC5 is required for nuclear export of a specific subset of mRNAs (including HoxB3, CBX2) in mouse embryo fibroblasts; these mRNAs co-purify with THOC5. HSP70 mRNA export requires THOC5 only under heat shock (42°C) but not normal (37°C) conditions. Conditional THOC5 knockout (Ad-Cre in MEF flox/flox cells), transcriptome analysis of cytoplasmic vs nuclear RNA fractions, RNA co-immunoprecipitation RNA (New York, N.Y.) High 21525145
2011 ATM kinase phosphorylates three serine residues in the PEST domain of THOC5 (S307/312/314), and DNA damage activates the ATM-p53 pathway to suppress THOC5 mRNA-binding capacity. The C-terminal domain of THOC5 (not the PEST phosphorylation sites) is necessary for mRNA binding regulation; ATM kinase inhibitor KU55933 blocks DNA damage-induced THOC5-mRNP dissociation. Site-directed mutagenesis (S307/312/314A), RNA immunoprecipitation, ATM inhibitor treatment, siRNA knockdown of ATM and p53 RNA (New York, N.Y.) High 21937706
2012 THOC5 Y225 phosphorylation is mediated by Src PTK and reversed by CD45 phosphatase; Y225 phosphorylation governs THOC5 mRNA binding activity; this phosphorylation is elevated in CML stem cells and is sensitive to imatinib/dasatinib; CXCL12 also induces Y225 phosphorylation and Y225 phosphorylation modulates cell motile response. Site-directed mutagenesis (Y225), RNA immunoprecipitation, kinase/phosphatase co-expression, patient sample analysis, migration assay Leukemia High 23032722
2013 THOC5 interacts with CFIm68 (large subunit of mammalian cleavage factor I) via direct protein-protein interaction; THOC5 depletion selectively attenuates expression of mRNAs using distal polyadenylation sites, phenocopying CFIm68 depletion, and reduces 5' CFIm68 ChIP-Seq peaks globally, indicating THOC5 controls polyadenylation site choice through co-transcriptional loading of CFIm68. Co-purification, co-immunoprecipitation, siRNA knockdown, microarray, ChIP-Seq Nucleic acids research High 23685434
2013 THOC5 localizes to nuclear speckles and translocates from the nucleus to cytoplasm during M-CSF-induced macrophage differentiation. THOC5 is recruited to chromatin at Ets1 loci, binds both unspliced and spliced Ets1 transcripts, and is required for processing/export of M-CSF-inducible mRNAs including Ets1 (without THOC5, unspliced Ets1 accumulates in the nucleus). Immunofluorescence, chromatin immunoprecipitation, RNA immunoprecipitation, tamoxifen-inducible conditional knockout, transcriptome analysis Cell death & disease High 24157873
2013 THOC5 is required for processing/export of a subset of Wnt target mRNAs (Sox9, Ascl2 but not Fn1) in intestinal cells, and these mRNAs bind THOC5 directly. THOC5 depletion impairs gut epithelial differentiation and self-renewal in vivo. Tamoxifen-inducible conditional knockout mice, RNA immunoprecipitation, intestinal phenotype analysis BMC cell biology High 24267292
2014 Upon serum stimulation, THOC5 forms a complex with polyadenylation-specific factor CPSF100 and is required for recruitment of CPSF100 to the 3'UTR of immediate-early gene targets (Id1, Id3, Wnt11, Myc, Smad7). Without THOC5, some IEG transcripts (Id1, Id3, Wnt11) are not released from chromatin, while others (Myc, Smad7) are released with shortened 3'UTRs due to alternative cleavage. Interactome analysis (THOC5 as bait), co-immunoprecipitation, ChIP, transcriptome analysis, THOC5 conditional knockout Nucleic acids research High 25274738
2022 THOC5 depletion decreases transcription elongation rates in vivo, alters RNA polymerase II binding across genes, and causes altered 3' cleavage of >50% of mRNAs. THOC5 is recruited near high-density Pol II sites. In slow Pol II cells, chromatin-associated THOC5 forms a complex with CDK12, DDX5, DDX17, and THOC6; CDK12/THOC5 interaction promotes CDK12 recruitment to R-loops in a THOC6-dependent manner. THOC5 depletion, elongation rate measurement in vivo, ChIP-seq for Pol II, Co-immunoprecipitation, R-loop analysis iScience High 36590164
2021 THOC2 promotes stem-like properties and radioresistance in triple-negative breast cancer cells in a THOC5-dependent manner by facilitating nuclear release of SOX2 and NANOG transcripts; THOC5 silencing decreases SOX2 and NANOG protein levels and depletes stem-like properties. siRNA knockdown of THOC2/THOC5, xenograft tumor assays, protein expression analysis Advanced science Medium 34708581
2022 THOC5 shuttles between nucleus and cytoplasm in an M-CSF signaling-dependent manner. THOC5 binds FICD (a proteolytic cleavage product of c-FMS receptor) and facilitates nuclear translocation of FICD. THOC5 knockdown suppresses osteoclast differentiation by reducing RANKL-induced FOS and NFATc1 expression. Subcellular fractionation, immunofluorescence, co-immunoprecipitation, siRNA knockdown, osteoclast differentiation assay European journal of cell biology Medium 35688054
2024 SF3B1 K700E cancer mutation attenuates the interaction between SF3B1 and THOC5, reducing THOC5 binding to a subset of mRNAs and inhibiting their nuclear export. Overexpression of THOC5 restores nuclear export of these mRNAs in SF3B1 K700E mutant cells. Co-immunoprecipitation, RNA immunoprecipitation, nuclear/cytoplasmic fractionation, THOC5 overexpression rescue Journal of biochemistry Medium 39259498
2024 LncBCL2L11 prevents binding of THOC6 to THOC5, causing THOC5 degradation; this promotes acylcarnitine accumulation in gallbladder cancer cells and cancer metastasis. RNA pull-down, RNA immunoprecipitation, Co-immunoprecipitation, Western blot, in vitro and in vivo functional assays Journal of translational medicine Medium 38519939

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Adaptor Aly and co-adaptor Thoc5 function in the Tap-p15-mediated nuclear export of HSP70 mRNA. The EMBO journal 117 19165146
2010 THOC5/FMIP, an mRNA export TREX complex protein, is essential for hematopoietic primitive cell survival in vivo. BMC biology 98 20051105
2011 Identification of mRNAs that are spliced but not exported to the cytoplasm in the absence of THOC5 in mouse embryo fibroblasts. RNA (New York, N.Y.) 56 21525145
2013 Human TREX component Thoc5 affects alternative polyadenylation site choice by recruiting mammalian cleavage factor I. Nucleic acids research 49 23685434
2021 THOC2 and THOC5 Regulate Stemness and Radioresistance in Triple-Negative Breast Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 46 34708581
1999 FMIP, a novel Fms-interacting protein, affects granulocyte/macrophage differentiation. Oncogene 42 10597251
2014 THOC5 controls 3'end-processing of immediate early genes via interaction with polyadenylation specific factor 100 (CPSF100). Nucleic acids research 33 25274738
2004 The M-CSF receptor substrate and interacting protein FMIP is governed in its subcellular localization by protein kinase C-mediated phosphorylation, and thereby potentiates M-CSF-mediated differentiation. Oncogene 33 15221008
2013 Transcriptional regulation of immediate-early gene response by THOC5, a member of mRNA export complex, contributes to the M-CSF-induced macrophage differentiation. Cell death & disease 30 24157873
2014 THOC5, a member of the mRNA export complex: a novel link between mRNA export machinery and signal transduction pathways in cell proliferation and differentiation. Cell communication and signaling : CCS 29 24410813
2006 FMIP controls the adipocyte lineage commitment of C2C12 cells by downmodulation of C/EBP alpha. Oncogene 28 16909111
2015 Depletion of three combined THOC5 mRNA export protein target genes synergistically induces human hepatocellular carcinoma cell death. Oncogene 23 26549021
2013 THOC5, a member of the mRNA export complex, contributes to processing of a subset of wingless/integrated (Wnt) target mRNAs and integrity of the gut epithelial barrier. BMC cell biology 22 24267292
2012 A pathway from leukemogenic oncogenes and stem cell chemokines to RNA processing via THOC5. Leukemia 19 23032722
2008 Nuclear localization of the pre-mRNA associating protein THOC7 depends upon its direct interaction with Fms tyrosine kinase interacting protein (FMIP). FEBS letters 17 19059247
2011 An ataxia-telangiectasia-mutated (ATM) kinase mediated response to DNA damage down-regulates the mRNA-binding potential of THOC5. RNA (New York, N.Y.) 16 21937706
2008 THOC5 spliceosome protein: a target for leukaemogenic tyrosine kinases that affects inositol lipid turnover. British journal of haematology 16 18373705
2008 THOC5 couples M-CSF receptor signaling to transcription factor expression. Cellular signalling 15 19015024
2016 mRNA export protein THOC5 as a tool for identification of target genes for cancer therapy. Cancer letters 14 26828015
2022 THOC5 complexes with DDX5, DDX17, and CDK12 to regulate R loop structures and transcription elongation rate. iScience 12 36590164
2013 THOC5: a novel gene involved in HDL-cholesterol metabolism. Journal of lipid research 12 24023261
2024 Acylcarnitines promote gallbladder cancer metastasis through lncBCL2L11-THOC5-JNK axis. Journal of translational medicine 8 38519939
2016 MPL W515L expression induces TGFβ secretion and leads to an increase in chemokinesis via phosphorylation of THOC5. Oncotarget 7 26919114
2019 Colla corii asini might upregulate ZNF471 and THOC5 by KRAB domain-containing zinc-finger protein pathway and THO complex subunit 5 pathway to improve anemia of pregnant women with β-thalassemia. Annals of hematology 5 31098739
2024 Resveratrol regulates Thoc5 to improve maternal immune activation-induced autism-like behaviors in adult mouse offspring. The Journal of nutritional biochemistry 4 38583499
2024 Cancer-associated SF3B1 mutations inhibit mRNA nuclear export by disrupting SF3B1-THOC5 interactions. Journal of biochemistry 2 39259498
2019 Polymorphism of the THOC5 of the transcription/export multiprotein complex and its correlation with the lipid and metabolic profile in middle-aged women. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 2 31402763
2025 Elevated THOC5 expression in liver cancer and its implications for tumor progression and therapeutic response. Frontiers in medicine 1 40901498
2025 Long non-coding RNA HMGCR suppresses vascular remodeling in streptozotocin-induced type 1 diabetic rats via interaction with THOC5. European journal of medical research 1 41024185
2022 THOC5 regulates human osteoclastogenesis. European journal of cell biology 1 35688054
2025 Targeting mRNA export complex macromolecules THO subunits (Thoc2 and Thoc5) for somatic cell reprograming. International journal of biological macromolecules 0 40107550