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Showing ALYREF — THOC4 is a alias.

ALYREF

THO complex subunit 4 · UniProt Q86V81

Length
257 aa
Mass
26.9 kDa
Annotated
2026-06-09
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALYREF (ALY/REF) is the metazoan mRNA export adaptor that couples nuclear mRNP maturation to nuclear export, recruited to spliced mRNPs in a splicing-dependent manner and capable of accelerating bulk mRNA export in vivo (PMID:11014198). Its loading onto RNA is driven by the DEAD-box helicase UAP56, which directly binds ALYREF and, in an ATP-dependent reaction, deposits it onto RNA before dissociating upon ATP hydrolysis—a chaperone-style handoff that also operates on intronless mRNAs (PMID:11675789, PMID:17984224, PMID:20844015). Within the TREX complex, ALYREF contacts THO subunits THOC2 and THOC5 and bridges UAP56 to the cap-binding protein CBP80, while a short conserved WxHD motif in an unstructured region coordinates simultaneous engagement of the exon junction complex (via eIF4A3) and the cap-binding complex on spliced mRNAs and directs nuclear speckle localization (PMID:23222130, PMID:26773052). ALYREF and the co-adaptor THOC5 occupy non-overlapping sites on the NTF2-like domain of the export receptor TAP/NXF1, and arginine methylation lowers ALYREF's RNA affinity to enable handover of the transcript to TAP/NXF1 (PMID:19165146, PMID:20129943). ALYREF additionally functions as a reader of 5-methylcytosine (m5C)-modified mRNA: it recognizes m5C marks deposited by NSUN2 and couples this epitranscriptomic modification to selective mRNA export (PMID:28418038). Its binding to ARS2 within the cap-binding complex constitutes an export-versus-degradation checkpoint, competing with the exosome cofactor hMTR4 to determine nuclear RNA fate (PMID:28801509). Beyond export, ALYREF can stabilize nuclear RNAs independently of export by protecting the poly(A) tail (PMID:22290432), promote histone pre-mRNA 3'-end processing through SLBP- and Lsm11-dependent U7-snRNP recruitment (PMID:30858280), and act as a transcriptional coactivator with LEF-1/AML-1 at the TCRα enhancer (PMID:9119228) and with MYCN at the USP3 promoter (PMID:33767157). ALYREF activity is regulated by nuclear Akt-mediated phosphorylation at Thr-219 and by phosphoinositide binding, which together control speckle residency and export function (PMID:18562279). In disease contexts, ALYREF stabilizes oncogenic m5C-marked transcripts in multiple cancers (PMID:33991457, PMID:36806253), and viral proteins including HSV-1 ICP27 and HVS ORF57 hijack ALYREF to route intronless viral RNAs into the TAP/NXF1 export pathway (PMID:12438613, PMID:24550725).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1997 Medium

    Before its export role was known, ALYREF was identified as a transcriptional coactivator, establishing an early and distinct nuclear function in gene activation.

    Evidence Yeast two-hybrid, Co-IP, and reporter assays linking ALY to LEF-1/AML-1 activation domains and TCRα enhancer activity

    PMID:9119228

    Open questions at the time
    • Does not establish whether coactivation is separable from RNA-handling functions
    • No structural basis for activation-domain recognition
  2. 2000 High

    Established ALYREF as a splicing-dependent mRNP component and bona fide mRNA export factor, defining its core cellular role.

    Evidence IP of spliced mRNPs, in vivo Xenopus oocyte export assays, shuttling assays

    PMID:11014198

    Open questions at the time
    • Mechanism of recruitment to mRNP not yet defined
    • Did not identify the export receptor it hands RNA to
  3. 2001 High

    Answered how ALYREF is recruited to spliced mRNPs by showing UAP56 directly binds and loads it, coupling splicing to export.

    Evidence Co-IP, in vitro binding, dominant-negative overexpression, ALY point-mutant rescue, export assays

    PMID:11675789

    Open questions at the time
    • Energetics of the loading reaction not yet resolved
    • Did not address intronless mRNA recruitment
  4. 2002 Medium

    Defined the limits of ALYREF's export role by showing EJC/REF1 is dispensable for bulk export in Drosophila, implying redundant adaptors.

    Evidence RNAi depletion in S2 cells with poly(A)+ FISH readout

    PMID:12438415

    Open questions at the time
    • Identity of redundant adaptors not established
    • Species-specific differences from mammals unresolved
  5. 2002 Medium

    Showed viral exploitation of ALYREF, with HSV-1 ICP27 relocating it to route intronless viral mRNAs into the TAP/NXF1 pathway.

    Evidence Co-IP, UV cross-linking, dominant-negative TAP and LMB assays, colocalization

    PMID:12438613

    Open questions at the time
    • ICP27 export shown to be ALYREF-independent, leaving ALYREF's necessity for viral RNA export unclear
    • No structural detail of the interaction
  6. 2007 High

    Resolved the biochemical logic of RNA loading: ATP-bound UAP56 contacts both RNA and ALYREF and chaperones loading onto intronless mRNA.

    Evidence In vitro RNA-binding and ATP hydrolysis assays, ATP-binding-deficient UAP56 mutant in oocytes

    PMID:17984224

    Open questions at the time
    • Stoichiometry on native mRNPs not defined
    • Selectivity for specific transcripts unaddressed
  7. 2008 Medium

    Identified post-translational regulation, showing nuclear Akt phosphorylates ALYREF at Thr-219 and that phosphoinositide binding controls speckle residency and export.

    Evidence In vitro kinase assay, T219 mutagenesis, siRNA, export and proliferation assays, phosphoinositide binding

    PMID:18562279

    Open questions at the time
    • Physiological signals upstream of nuclear Akt toward ALYREF unclear
    • Single lab; phosphoinositide-binding interface not mapped
  8. 2009 Medium

    Mapped the ALYREF–NXF1 handoff geometry, showing ALYREF and THOC5 bind non-overlapping sites on the NXF1 NTF2-like domain.

    Evidence Recombinant protein binding, RNAi, RNA-IP, in vitro RNA binding

    PMID:19165146

    Open questions at the time
    • Transcript selectivity beyond HSP70 not generalized
    • Order of binding events on NXF1 unresolved
  9. 2010 High

    Reconstituted ATP-dependent TREX assembly, showing UAP56 bridges a trimeric complex with ALYREF and CIP29 and links THO to both.

    Evidence Proteomics of immunopurified TREX, in vitro reconstitution with recombinant proteins, ATP-dependence assays

    PMID:20844015

    Open questions at the time
    • Dynamics of complex disassembly during export unresolved
    • Spatial coupling to spliceosome not reconstituted
  10. 2010 Medium

    Explained the RNA-to-receptor handover, showing arginine methylation lowers ALYREF RNA affinity to allow TAP/NXF1 to displace it from mRNA.

    Evidence MS mapping of methylation sites, in vitro/in vivo RNA-binding and export assays

    PMID:20129943

    Open questions at the time
    • Methyltransferase responsible not identified here
    • Regulation of methylation timing unknown
  11. 2012 Medium

    Detailed TREX architecture by showing ALYREF directly binds THOC2/THOC5 and that ALY and THO mutually require each other and link UAP56 to CBP80.

    Evidence Systematic RNAi, Co-IP, spliced-mRNA association and export assays

    PMID:23222130

    Open questions at the time
    • Direct vs. indirect CBP80 contact not distinguished here
    • Single lab
  12. 2012 Medium

    Uncovered an export-independent function, showing ALYREF can stabilize nuclear RNA by protecting the poly(A) tail.

    Evidence MS2 tethering to KSHV PAN RNA, half-life and poly(A) tail measurements

    PMID:22290432

    Open questions at the time
    • Mechanism of poly(A) protection not biochemically defined
    • Generality to cellular RNAs untested
  13. 2014 High

    Provided atomic-resolution insight into viral RNA hijacking, defining how HVS ORF57 transfers viral RNA to ALYREF in a ternary complex.

    Evidence NMR structure of the ORF57-ALYREF interface, UV cross-linking, mutagenesis, competition assays

    PMID:24550725

    Open questions at the time
    • Cellular RNA-recognition mode of ALYREF N-terminus not structurally generalized
    • Does not address full mRNP context
  14. 2016 Medium

    Identified the WxHD motif as the structural hub coordinating EJC (eIF4A3) and cap (CBP80) engagement during export-complex assembly on spliced mRNAs.

    Evidence Conserved-motif analysis, in vitro splicing, mutagenesis, Co-IP, speckle localization, export reporter

    PMID:26773052

    Open questions at the time
    • How a single short motif achieves multiple contacts unresolved
    • Structural model of assembled complex absent
  15. 2017 High

    Defined ALYREF as an m5C reader, coupling NSUN2-deposited methylation to selective mRNA export — a major expansion of its mechanism.

    Evidence In vitro m5C binding, RIP, fractionation, export assays, NSUN2 methyltransferase-dead rescue, m5C-seq

    PMID:28418038

    Open questions at the time
    • Structural basis of m5C recognition not defined
    • Fraction of cellular export that is m5C-dependent unquantified
  16. 2017 Medium

    Positioned ALYREF at an export-versus-degradation decision point by showing hMTR4 competes with it for ARS2 binding.

    Evidence Co-IP competition assays, RNAi, RNA-seq, nuclear RNA quantification

    PMID:28801509

    Open questions at the time
    • What biases the competition for individual transcripts unknown
    • Single lab
  17. 2019 Medium

    Extended ALYREF's role to histone mRNA biogenesis, linking it to SLBP- and Lsm11-dependent 3'-end processing as well as export.

    Evidence RIP, reciprocal Co-IP, 3'-end processing and export assays, RNAi

    PMID:30858280

    Open questions at the time
    • Mechanistic order of processing vs. recruitment only partly resolved
    • Single lab
  18. 2021 Medium

    Connected ALYREF to oncogenic gene regulation, including m5C-dependent stabilization of PKM2 mRNA and coactivation of MYCN at the USP3 promoter.

    Evidence RIP/RIP-seq, ChIP and ubiquitination assays, luciferase reporters, in vitro and in vivo cancer models

    PMID:33767157 PMID:33991457

    Open questions at the time
    • Whether export vs. stabilization drives the oncogenic effect not fully separated
    • Single-lab cancer-context studies
  19. 2023 Medium

    Mapped a domain (K171) required for hypermethylated-m5C recognition and showed ALYREF can promote splicing and stabilization of target transcripts including a writer-reader loop with NSUN2 mRNA.

    Evidence RNA BisSeq, RNA-seq, RIP-seq, K171 domain mutagenesis, organoid and xenograft models

    PMID:36806253

    Open questions at the time
    • Structural definition of the K171 m5C-binding pocket absent
    • Generality of the NSUN2 feedback loop untested
  20. 2024 Low

    Multiple cancer studies extended the m5C-reader model to additional transcripts and cooperating factors (e.g., ELAVL1), establishing recurrent oncogenic ALYREF-m5C axes.

    Evidence RIP/RIP-Bis-seq, RNA stability/export assays, Co-IP, in vivo tumor models across HCC, PDAC, CRC and NPC

    PMID:38164181 PMID:38402198 PMID:39117671 PMID:39455812

    Open questions at the time
    • Largely RIP-based binding without mutagenesis of m5C sites or ALYREF interface
    • Single-lab, context-specific; mechanistic cascades only partly validated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ALYREF's distinct activities — TREX-mediated bulk export, m5C-reader selectivity, transcriptional coactivation, RNA stabilization, and histone-processing — are partitioned and regulated within a single nucleus remains unresolved.
  • No structural model integrating m5C recognition with the TREX export interface
  • Rules governing transcript-specific m5C-dependent versus splicing-dependent recruitment unknown
  • Mechanistic separation of export-coupled vs. export-independent (stabilization, transcription) roles incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0060090 molecular adaptor activity 4 GO:0140110 transcription regulator activity 2 GO:0140299 molecular sensor activity 1
Localization
GO:0005654 nucleoplasm 3 GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-1643685 Disease 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-9609507 Protein localization 3
Partners
CBP80EIF4A3ELAVL1NSUN2NXF1THOC2THOC5UAP56
Complex memberships
THO complexTREX complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ALY (ALYREF) is the metazoan homologue of yeast mRNA export factor Yra1p and is recruited to mRNP complexes in a splicing-dependent manner. ALY associates with spliced mRNPs but not with pre-assembled intronless mRNPs or hnRNP complexes, and shuttles between nucleus and cytoplasm. Excess recombinant ALY increases the rate and efficiency of mRNA export in vivo. Immunoprecipitation of spliced mRNPs, in vivo microinjection/export assays in Xenopus oocytes, nuclear-cytoplasmic shuttling assays Nature High 11014198
2001 The DEAD-box helicase UAP56 directly and specifically interacts with ALY/ALYREF and is present together with ALY in the spliced mRNP. Excess UAP56 acts as a dominant-negative inhibitor of mRNA export and blocks recruitment of ALY to the spliced mRNP. An ALY mutation that abolishes UAP56 interaction prevents ALY recruitment to spliced mRNP, demonstrating that UAP56 recruits ALY to couple splicing and export. Co-immunoprecipitation, in vitro binding assays, dominant-negative overexpression, mRNA export assays, ALY point mutant analysis Nature High 11675789
1997 ALY (ALYREF) specifically associates with the activation domains of LEF-1 and AML-1 transcription factors, can increase DNA binding by both LEF-1 and AML proteins, and is required for TCRα enhancer activity. Overexpression of ALY stimulates TCRα enhancer activity in non-lymphoid cells; antisense depletion virtually eliminates TCRα enhancer activity in T cells. Yeast two-hybrid cloning, co-immunoprecipitation, overexpression and antisense knockdown in transfection assays, reporter gene assays Genes & development Medium 9119228
2002 REF1/ALYREF and additional exon junction complex (EJC) proteins are dispensable for bulk mRNA export in Drosophila cells. Nuclear mRNA accumulation is only partially observed when REF1 and RNPS1 are co-depleted or all EJC proteins are simultaneously depleted, indicating that additional adaptor proteins mediate NXF1-mRNA interaction in metazoa independently of REF1. RNAi depletion in Drosophila S2 cells, fluorescence in situ hybridization for poly(A)+ RNA localization The Journal of cell biology Medium 12438415
2007 ALY/REF is preferentially associated with intronless mRNAs in the nucleus. UAP56 stimulates ALY/REF binding to intronless mRNA in vitro in an ATP-dependent manner. ATP activates RNA-binding activity of UAP56 itself; ATP-bound UAP56 contacts both RNA and ALY/REF simultaneously and cooperatively stimulates UAP56 ATPase activity, consistent with a chaperone model in which ATP-bound UAP56 loads ALY/REF onto RNA then dissociates upon ATP hydrolysis. RNA-binding assays in vitro, ATP hydrolysis assays, dominant-negative mutant (ATP-binding-deficient UAP56) export inhibition in Xenopus oocytes Molecular and cellular biology High 17984224
2008 ALY/ALYREF is a physiological substrate of nuclear Akt kinase, which phosphorylates ALY at threonine-219. Nuclear PI3K/Akt signaling regulates ALY's subnuclear speckle residency, mRNA export activity, and cell proliferation. ALY also binds phosphoinositides; phosphoinositide binding (but not Akt phosphorylation) dictates nuclear speckle residency, while both phosphorylation and phosphoinositide binding are required for full mRNA export and proliferation functions. In vitro kinase assay, site-directed mutagenesis (T219 mutant), siRNA knockdown, mRNA export assays, cell proliferation assays, phosphoinositide-binding assay Proceedings of the National Academy of Sciences of the United States of America Medium 18562279
2009 Aly/ALYREF and co-adaptor Thoc5 can simultaneously bind non-overlapping sites on the middle (Ntf2-like) domain of the nuclear export receptor Tap/NXF1. Nuclear export of HSP70 mRNA specifically depends on both Thoc5 and Aly. Thoc5 exhibits in vitro RNA-binding activity and associates with HSP70 mRNPs as part of the THO complex. Binding assays with recombinant proteins, RNAi knockdown, RNA immunoprecipitation, in vitro RNA-binding assay The EMBO journal Medium 19165146
2010 Arginine methylation of REF/ALYREF (mapped by mass spectrometry) reduces its RNA-binding activity in vitro and in vivo without affecting the REF:TAP interaction. This reduced RNA-binding affinity in the methylated state is required for efficient displacement of RNA from REF by TAP/NXF1 in vivo, facilitating handover of mRNA to the export receptor. Mass spectrometry mapping of methylation sites, in vitro RNA-binding assays with methylated vs. unmethylated REF, in vivo RNA-binding assays, mRNA export assays Nucleic acids research Medium 20129943
2010 ATP is strictly required for the interaction between UAP56 and both Aly/ALYREF and CIP29 during TREX complex assembly. Using recombinant proteins, UAP56 bridges an ATP-dependent trimeric complex with Aly and CIP29. UAP56 mediates ATP-dependent interaction between the THO complex and both Aly and CIP29. Proteomic analysis of immunopurified TREX, in vitro reconstitution of trimeric complex with recombinant proteins expressed in E. coli, ATP-dependence assays Genes & development High 20844015
2012 ALYREF directly interacts with THO subunits Thoc2 and Thoc5. Aly, THO, and UAP56 are all required for TREX assembly and for association of UAP56 with the spliced mRNA (but not pre-mRNA). Aly and THO require each other to associate with spliced mRNA. Both Aly and THO link UAP56 to the cap-binding protein CBP80. Systematic RNAi depletion, co-immunoprecipitation, spliced mRNA-association assays, mRNA export assays Nucleic acids research Medium 23222130
2012 REF/ALYREF can stabilize nuclear RNAs independently of promoting their export. Tethering REF/ALYREF to the KSHV PAN RNA increases its nuclear abundance and half-life but is insufficient to promote export. REF/ALYREF appears to protect the poly(A) tail from deadenylation, and REF-stabilized transcripts undergo further adenylation over time. Tethering assay (REF fused to MS2 coat protein), RNA half-life measurements, poly(A) tail length analysis, nuclear RNA abundance quantification Molecular and cellular biology Medium 22290432
2016 A short conserved WxHD motif in an unstructured region of ALYREF is required for RNA binding and for interaction with both eIF4A3 (EJC component) and CBP80 (cap-binding complex). Mutation of this motif impairs proper localization to nuclear speckles and reduces export of a spliced reporter mRNA, indicating this motif coordinates EJC- and cap-dependent assembly of export complexes on spliced mRNAs. Computational discovery of conserved motifs, in vitro splicing assays, site-directed mutagenesis, co-immunoprecipitation, nuclear speckle localization by fluorescence microscopy, spliced mRNA export reporter assay Nucleic acids research Medium 26773052
2017 m5C modification in mRNAs is specifically recognized by ALYREF as an mRNA export adaptor, as demonstrated by in vitro binding assays and in vivo RNA immunoprecipitation. m5C formation is mainly catalyzed by NSUN2, and NSUN2 modulates ALYREF's nuclear-cytoplasmic shuttling and RNA-binding affinity. Depletion of NSUN2 reduces ALYREF-mediated mRNA export, which can be restored by wild-type but not methyltransferase-defective NSUN2, establishing ALYREF as an m5C reader that links RNA methylation to mRNA export. In vitro m5C RNA-binding assays, RNA immunoprecipitation (RIP), nuclear-cytoplasmic fractionation, mRNA export assays, NSUN2 reconstitution with methyltransferase-defective mutant, m5C-seq transcriptome profiling Cell research High 28418038
2017 hMTR4 (exosome cofactor) directly competes with ALYREF for binding to ARS2, a component of the cap-binding complex (CBC). This competition determines whether an RNA is degraded by the nuclear exosome or exported to the cytoplasm, establishing ALYREF's ARS2-binding as a critical checkpoint for nuclear RNA fate. Co-immunoprecipitation competition assays, RNAi knockdown, RNA-seq, nuclear RNA abundance measurements The EMBO journal Medium 28801509
2019 ALYREF binds a region adjacent to the stem-loop (SL) structure on replication-dependent histone mRNAs. The SL-binding protein (SLBP) directly interacts with ALYREF and promotes its recruitment. ALYREF promotes histone pre-mRNA 3'-end processing by facilitating U7-snRNP recruitment through physical interaction with the U7-snRNP-specific component Lsm11, and together with other TREX components enhances histone mRNA nuclear export. 3'-end processing in turn promotes ALYREF recruitment. RNA immunoprecipitation, co-immunoprecipitation of ALYREF-SLBP and ALYREF-Lsm11 interactions, 3'-end processing assays, mRNA export assays, RNAi knockdown The EMBO journal Medium 30858280
2021 ALYREF forms a nuclear coactivator complex with MYCN that stimulates transcription of USP3. Increased USP3 levels reduce K-48- and K-63-linked ubiquitination of MYCN, stabilizing MYCN protein. ALYREF is required for MYCN-driven effects on the malignant phenotype and for USP3's effect on MYCN stability, defining an ALYREF-MYCN-USP3 axis in neuroblastoma. Co-immunoprecipitation of ALYREF-MYCN complex, ChIP/transcription assays for USP3, ubiquitination assays, transgenic neuroblastoma models in vitro and in vivo, RNAi knockdown Nature communications Medium 33767157
2021 ALYREF stabilizes PKM2 mRNA by binding to m5C sites in the 3'-UTR of PKM2 mRNA (demonstrated by RNA immunoprecipitation and RIP-seq). Overexpression of ALYREF promotes bladder cancer cell proliferation via PKM2-mediated glycolysis. HIF-1α indirectly upregulates PKM2 expression by transcriptionally activating ALYREF. RNA immunoprecipitation (RIP), RNA-seq, dual-luciferase reporter assays, Western blotting, in vitro and in vivo cancer cell assays Cancer communications Medium 33991457
2021 ALYREF drives glioblastoma cell proliferation via stabilization of MYC mRNA (demonstrated by CLIP assay) and activation of Wnt/β-catenin signaling. MYC transcriptionally regulates ALYREF expression (by ChIP assay), creating a positive feedback loop. ALYREF depletion reduces GBM tumor formation in vivo. ChIP assay, CLIP assay, RNA stability assays, siRNA knockdown, in vitro proliferation and in vivo tumor formation assays OncoTargets and therapy Low 33447056
2022 ALYREF binds to the NEAT1 promoter region to enhance global NEAT1 transcriptional activity, and also stabilizes CPSF6 (a protein that selectively promotes the short NEAT1 isoform) and directly binds and stabilizes the short NEAT1 isoform. This selectively fine-tunes the short NEAT1 isoform expression in breast cancer. ChIP assay for ALYREF at NEAT1 promoter, RNA-binding/stability assays, CPSF6 protein level measurement upon ALYREF knockdown, transcriptional profiling, orthotopic mouse model Cellular and molecular life sciences Low 35776213
2023 ALYREF specifically binds hypermethylated m5C sites in RABL6 and TK1 mRNA via its K171 domain and controls UCB malignancy by promoting hypermethylated RABL6 and TK1 mRNA splicing and stabilization. ALYREF also recognizes hypermethylated m5C sites in NSUN2 mRNA, resulting in NSUN2 upregulation and creating a cross-regulatory loop between the m5C writer and reader. RNA bisulfite sequencing (BisSeq), RNA-seq, RIP-seq, patient-derived organoids, orthotopic xenograft models, domain mutagenesis (K171) Cell death & disease Medium 36806253
2024 ALYREF directly binds m5C modification sites in the 3'-UTR of EGFR mRNA, stabilizing EGFR mRNA and consequently activating the STAT3 signaling pathway in hepatocellular carcinoma cells. RNA immunoprecipitation (RIP), RNA stability assays, m5C site identification, in vitro and in vivo functional assays International journal of biological sciences Low 38164181
2024 ALYREF recognizes m5C sites in JunD mRNA, maintaining JunD mRNA stability and upregulating SLC7A5 transcription, which depletes amino acids in the tumor microenvironment and restricts CD8+ T cell function in pancreatic ductal adenocarcinoma. RNA immunoprecipitation, RNA stability assays, in vivo tumor growth assays, immune cell function assays, tissue microarray Cell death discovery Low 38402198
2024 ALYREF forms a complex with ELAVL1 (HuR) to cooperatively promote m5C recognition and nuclear export of RPS6KB2 and RPTOR mRNAs in colorectal cancer cells. E2F6 transcriptionally activates ALYREF expression. RIP-Bis-seq, RNA-seq, Co-immunoprecipitation of ALYREF-ELAVL1 complex, RNA export assays, ChIP for E2F6 at ALYREF promoter NPJ precision oncology Low 39455812
2019 Drosophila Ref1 (orthologue of human ALYREF) genetically interacts with TDP-43 and C9orf72 GGGGCC repeat expansion: Ref1 downregulation mitigates toxicity from both disease proteins by lowering their mRNA and protein levels. Expression of TDP-43 or GGGGCC repeats increases endogenous Ref1 mRNA levels. Human ALYREF protein is upregulated by immunohistochemistry in ALS motor neurons. Drosophila genetic screen, RNAi knockdown, mRNA/protein level quantification, immunohistochemistry of human ALS tissue Acta neuropathologica communications Low 31036086
2024 ALYREF promotes NPC metastasis by binding m5C-modified NOTCH1 mRNA, enhancing NOTCH1 mRNA stability in an m5C modification-dependent manner, thereby activating the NOTCH signaling pathway. RNA immunoprecipitation, RNA stability assays, m5C sequencing, in vitro invasion/migration assays, in vivo metastasis model Cell death & disease Low 39117671
2020 ALYREF, as an m5C reader protein, plays an important role in regulating murine leukemia virus (MLV) replication. m5C is highly enriched in viral genomic RNA relative to cellular mRNAs, and ALYREF knockdown reduces viral production. Mass spectrometry, m5C sequencing at single-nucleotide resolution, siRNA knockdown of ALYREF, viral titer assays Journal of virology Low 32321818
2002 HSV-1 ICP27 interacts with ALY/REF in infected mammalian cells and recruits ALY/REF from spliceosomes to viral transcription sites. This interaction directs viral intronless mRNAs to the TAP/NXF1 export pathway. ICP27 interacts directly with TAP/NXF1 independently of ALY/REF bridging, and this TAP/NXF1 interaction (not the ALY/REF interaction) is required for ICP27 nuclear export. Co-immunoprecipitation, UV cross-linking, dominant-negative TAP export assay, LMB sensitivity assay, immunofluorescence colocalization Journal of virology Medium 12438613
2014 NMR structure of the HVS ORF57-ALYREF interface was determined at atomic resolution. An α-helix in ORF57 competitively displaces viral RNA from ORF57 when ALYREF is present, while the flexible N-terminal domain of ALYREF engages the viral RNA, creating a ternary ALYREF-ORF57-RNA complex. UV cross-linking and mutagenesis confirmed individual ORF57 residues involved in RNA recognition and the RNA-transfer mechanism. NMR structure determination of ORF57-ALYREF interface, UV cross-linking, site-directed mutagenesis, RNA-binding competition assays PLoS pathogens High 24550725
2022 m5C modification of YBX2 and SMO mRNAs is recognized by ALYREF, which exports these mRNAs to the cytoplasm, increasing YBX2 and SMO protein levels. This mechanism inhibits adipogenesis and promotes myogenesis respectively via ALYREF-m5C-YBX2 and ALYREF-m5C-SMO axes. RNA bisulfite sequencing, RNA immunoprecipitation, nuclear-cytoplasmic fractionation, RNA export assays, in vitro adipogenesis/myogenesis differentiation assays Cellular and molecular life sciences Low 35962235

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 5-methylcytosine promotes mRNA export - NSUN2 as the methyltransferase and ALYREF as an m5C reader. Cell research 878 28418038
2000 Going APE over ref-1. Mutation research 478 11018583
2000 The protein Aly links pre-messenger-RNA splicing to nuclear export in metazoans. Nature 419 11014198
2009 The many functions of APE1/Ref-1: not only a DNA repair enzyme. Antioxidants & redox signaling 417 18976116
2001 Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly. Nature 331 11675789
1994 The redox and DNA-repair activities of Ref-1 are encoded by nonoverlapping domains. Proceedings of the National Academy of Sciences of the United States of America 326 7506414
2005 The intracellular localization of APE1/Ref-1: more than a passive phenomenon? Antioxidants & redox signaling 324 15706084
1994 A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice. European journal of immunology 277 8299692
2021 The role of the HIF-1α/ALYREF/PKM2 axis in glycolysis and tumorigenesis of bladder cancer. Cancer communications (London, England) 256 33991457
1997 ALY, a context-dependent coactivator of LEF-1 and AML-1, is required for TCRalpha enhancer function. Genes & development 255 9119228
2007 The DNA base excision repair protein Ape1/Ref-1 as a therapeutic and chemopreventive target. Molecular aspects of medicine 226 17560642
2009 Transcriptional regulatory functions of mammalian AP-endonuclease (APE1/Ref-1), an essential multifunctional protein. Antioxidants & redox signaling 216 18715144
1999 Ref-1 regulates the transactivation and pro-apoptotic functions of p53 in vivo. The EMBO journal 201 10523305
2002 REF1/Aly and the additional exon junction complex proteins are dispensable for nuclear mRNA export. The Journal of cell biology 168 12438415
2010 ATP is required for interactions between UAP56 and two conserved mRNA export proteins, Aly and CIP29, to assemble the TREX complex. Genes & development 148 20844015
2002 ICP27 interacts with the RNA export factor Aly/REF to direct herpes simplex virus type 1 intronless mRNAs to the TAP export pathway. Journal of virology 143 12438613
2012 APE1/Ref-1 role in redox signaling: translational applications of targeting the redox function of the DNA repair/redox protein APE1/Ref-1. Current molecular pharmacology 141 22122463
2014 APE1/Ref-1 as an emerging therapeutic target for various human diseases: phytochemical modulation of its functions. Experimental & molecular medicine 136 25033834
2009 Adaptor Aly and co-adaptor Thoc5 function in the Tap-p15-mediated nuclear export of HSP70 mRNA. The EMBO journal 118 19165146
2012 Aly and THO are required for assembly of the human TREX complex and association of TREX components with the spliced mRNA. Nucleic acids research 114 23222130
2000 Alterations in the expression of the DNA repair/redox enzyme APE/ref-1 in epithelial ovarian cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 112 10690545
2000 Alymphoplasia (aly)-type nuclear factor kappaB-inducing kinase (NIK) causes defects in secondary lymphoid tissue chemokine receptor signaling and homing of peritoneal cells to the gut-associated lymphatic tissue system. The Journal of experimental medicine 102 10790423
2007 ATP-dependent recruitment of export factor Aly/REF onto intronless mRNAs by RNA helicase UAP56. Molecular and cellular biology 98 17984224
2017 Exosome cofactor hMTR4 competes with export adaptor ALYREF to ensure balanced nuclear RNA pools for degradation and export. The EMBO journal 93 28801509
2012 APE1/Ref-1 regulates STAT3 transcriptional activity and APE1/Ref-1-STAT3 dual-targeting effectively inhibits pancreatic cancer cell survival. PloS one 90 23094050
2003 The Ref/Aly proteins are dispensable for mRNA export and development in Caenorhabditis elegans. RNA (New York, N.Y.) 90 12810921
2008 Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY. Proceedings of the National Academy of Sciences of the United States of America 86 18562279
2005 ICP27 recruits Aly/REF but not TAP/NXF1 to herpes simplex virus type 1 transcription sites although TAP/NXF1 is required for ICP27 export. Journal of virology 85 15767397
2023 m5C-dependent cross-regulation between nuclear reader ALYREF and writer NSUN2 promotes urothelial bladder cancer malignancy through facilitating RABL6/TK1 mRNAs splicing and stabilization. Cell death & disease 84 36806253
1998 Ref-1 controls pax-8 DNA-binding activity. Biochemical and biophysical research communications 80 9813166
2023 LINC02159 promotes non-small cell lung cancer progression via ALYREF/YAP1 signaling. Molecular cancer 79 37537569
2016 A short conserved motif in ALYREF directs cap- and EJC-dependent assembly of export complexes on spliced mRNAs. Nucleic acids research 78 26773052
2013 Emerging roles of the nucleolus in regulating the DNA damage response: the noncanonical DNA repair enzyme APE1/Ref-1 as a paradigmatical example. Antioxidants & redox signaling 78 23879289
2003 APE/Ref-1 and the mammalian response to genotoxic stress. Toxicology 76 14599768
2014 Hevea brasiliensis REF (Hev b 1) and SRPP (Hev b 3): An overview on rubber particle proteins. Biochimie 72 25019490
2001 Oxidative cellular damage and the reduction of APE/Ref-1 expression after experimental traumatic brain injury. Neurobiology of disease 71 11447995
2011 Differential expression of THOC1 and ALY mRNP biogenesis/export factors in human cancers. BMC cancer 67 21329510
2006 Cooperative activity of Ref-1/APE and ERp57 in reductive activation of transcription factors. Free radical biology & medicine 66 16962936
2021 An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability. Nature communications 65 33767157
2014 Stress conditions promote yeast Gap1 permease ubiquitylation and down-regulation via the arrestin-like Bul and Aly proteins. The Journal of biological chemistry 65 24942738
2000 Human APE/Ref-1 protein. The international journal of biochemistry & cell biology 63 11084372
2015 APE1/Ref-1 as a Serological Biomarker for the Detection of Bladder Cancer. Cancer research and treatment 59 25672588
2010 Arginine methylation of REF/ALY promotes efficient handover of mRNA to TAP/NXF1. Nucleic acids research 55 20129943
2022 APE1/Ref-1 Role in Inflammation and Immune Response. Frontiers in immunology 54 35296074
2000 Immunodeficiency of alymphoplasia mice (aly/aly) in vivo: structural defect of secondary lymphoid organs and functional B cell defect. European journal of immunology 52 11069060
2003 Transcriptional activation in Drosophila spermatogenesis involves the mutually dependent function of aly and a novel meiotic arrest gene cookie monster. Development (Cambridge, England) 51 12490562
2008 APE1/Ref-1 regulates PTEN expression mediated by Egr-1. Free radical research 50 18324520
2009 The cellular RNA export receptor TAP/NXF1 is required for ICP27-mediated export of herpes simplex virus 1 RNA, but the TREX complex adaptor protein Aly/REF appears to be dispensable. Journal of virology 49 19369354
2004 BeF(x) stops the chaperonin cycle of GroEL-GroES and generates a complex with double folding chambers. The Journal of biological chemistry 47 15347650
2019 ALYREF links 3'-end processing to nuclear export of non-polyadenylated mRNAs. The EMBO journal 46 30858280
2017 Inhibitors of nuclease and redox activity of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1). Bioorganic & medicinal chemistry 45 28161249
2012 ALY as a potential contributor to metastasis in human oral squamous cell carcinoma. Journal of cancer research and clinical oncology 45 23242234
2021 Multi-Omic Analyses of the m5C Regulator ALYREF Reveal Its Essential Roles in Hepatocellular Carcinoma. Frontiers in oncology 44 34367948
2020 5-Methylcytosine RNA Modifications Promote Retrovirus Replication in an ALYREF Reader Protein-Dependent Manner. Journal of virology 44 32321818
2024 ALYREF-mediated RNA 5-Methylcytosine modification Promotes Hepatocellular Carcinoma Progression Via Stabilizing EGFR mRNA and pSTAT3 activation. International journal of biological sciences 43 38164181
2019 Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration. Redox biology 43 30802716
2018 Ref-1/APE1 Inhibition with Novel Small Molecules Blocks Ocular Neovascularization. The Journal of pharmacology and experimental therapeutics 43 30076264
2007 Bilirubin-induced cell toxicity involves PTEN activation through an APE1/Ref-1-dependent pathway. Journal of molecular medicine (Berlin, Germany) 41 17479230
2022 ALYREF, a novel factor involved in breast carcinogenesis, acts through transcriptional and post-transcriptional mechanisms selectively regulating the short NEAT1 isoform. Cellular and molecular life sciences : CMLS 40 35776213
2016 Dynamic Regulation of APE1/Ref-1 as a Therapeutic Target Protein. Chonnam medical journal 40 27231670
2024 HnRNPA2B1 ISGylation Regulates m6A-Tagged mRNA Selective Export via ALYREF/NXF1 Complex to Foster Breast Cancer Development. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 38 38626369
2023 ALYREF (Aly/REF export factor): A potential biomarker for predicting cancer occurrence and therapeutic efficacy. Life sciences 38 38135116
2018 ALY RNA-Binding Proteins Are Required for Nucleocytosolic mRNA Transport and Modulate Plant Growth and Development. Plant physiology 38 29540591
2022 mRNA m5C inhibits adipogenesis and promotes myogenesis by respectively facilitating YBX2 and SMO mRNA export in ALYREF-m5C manner. Cellular and molecular life sciences : CMLS 36 35962235
2012 Viral factors reveal a role for REF/Aly in nuclear RNA stability. Molecular and cellular biology 36 22290432
2001 Effects of the NIK aly mutation on NF-kappaB activation by the Epstein-Barr virus latent infection membrane protein, lymphotoxin beta receptor, and CD40. The Journal of biological chemistry 35 11278268
2019 Antitumor Activity and Mechanistic Characterization of APE1/Ref-1 Inhibitors in Bladder Cancer. Molecular cancer therapeutics 34 31413178
1997 The structure and functions of the HAP1/Ref-1 protein. Oncology research 34 9406232
2000 Cloning and sequence analysis of a gene (aly PG) encoding poly(alpha-L-guluronate)lyase from Corynebacterium sp. strain ALY-1. Journal of bioscience and bioengineering 30 16232727
2017 APE1/Ref-1 Inhibits Phosphate-Induced Calcification and Osteoblastic Phenotype Changes in Vascular Smooth Muscle Cells. International journal of molecular sciences 26 28946662
2024 ALYREF-JunD-SLC7A5 axis promotes pancreatic ductal adenocarcinoma progression through epitranscriptome-metabolism reprogramming and immune evasion. Cell death discovery 25 38402198
2024 ALYREF promotes the metastasis of nasopharyngeal carcinoma by increasing the stability of NOTCH1 mRNA. Cell death & disease 25 39117671
2013 The interaction of the cellular export adaptor protein Aly/REF with ICP27 contributes to the efficiency of herpes simplex virus 1 mRNA export. Journal of virology 25 23637401
2024 New Ref-1/APE1 targeted inhibitors demonstrating improved potency for clinical applications in multiple cancer types. Pharmacological research 24 38311014
2016 P1 Ref Endonuclease: A Molecular Mechanism for Phage-Enhanced Antibiotic Lethality. PLoS genetics 24 26765929
2001 ApeI/Ref-I expression and cellular localization in human thyroid carcinoma cell lines. Journal of endocrinological investigation 24 11314755
2024 The APE1/REF-1 and the hallmarks of cancer. Molecular biology reports 23 38165468
2021 ALYREF Drives Cancer Cell Proliferation Through an ALYREF-MYC Positive Feedback Loop in Glioblastoma. OncoTargets and therapy 23 33447056
2014 Competitive and cooperative interactions mediate RNA transfer from herpesvirus saimiri ORF57 to the mammalian export adaptor ALYREF. PLoS pathogens 23 24550725
2022 Pharmacological inhibition of Ref-1 enhances the therapeutic sensitivity of papillary thyroid carcinoma to vemurafenib. Cell death & disease 22 35136031
2021 Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy. International journal of molecular sciences 22 34638620
2009 ICP27 phosphorylation site mutants display altered functional interactions with cellular export factors Aly/REF and TAP/NXF1 but are able to bind herpes simplex virus 1 RNA. Journal of virology 22 20015986
1995 Ref-1 expression in adult mammalian neurons and astrocytes. Neuroscience letters 22 7644143
2021 Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours. British journal of cancer 21 33658640
2021 APE1/Ref-1 as a Novel Target for Retinal Diseases. Journal of cellular signaling 21 34322687
2014 5-HMF prevents against oxidative injury via APE/Ref-1. Free radical research 21 25363495
2012 Binding of cellular export factor REF/Aly by Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein is not required for efficient KSHV lytic replication. Journal of virology 21 22761374
2019 Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies. Acta neuropathologica communications 20 31036086
2019 The extracellular role of Ref-1 as anti-inflammatory function in lipopolysaccharide-induced septic mice. Free radical biology & medicine 20 31100475
2009 APE1/Ref-1: versatility in progress. Antioxidants & redox signaling 20 18715142
2009 HIF-1 attenuates Ref-1 expression in endothelial cells: reversal by siRNA and inhibition of geranylgeranylation. Vascular pharmacology 20 19524065
1994 The alymphoplasia (aly) mutation co-segregates with the intercellular adhesion molecule-2 (lcam-2) on mouse chromosome 11. International immunology 20 7947467
2024 ALYREF recruits ELAVL1 to promote colorectal tumorigenesis via facilitating RNA m5C recognition and nuclear export. NPJ precision oncology 19 39455812
2017 Ref-1/APE1 as a Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia. Molecular cancer therapeutics 19 28446640
2021 New Horizons for the Roles and Association of APE1/Ref-1 and ABCA1 in Atherosclerosis. Journal of inflammation research 18 34703267
2020 Plasma APE1/Ref-1 Correlates with Atherosclerotic Inflammation in ApoE-/- Mice. Biomedicines 18 32967121
2010 Reporter enzyme fluorescence (REF) imaging and quantification of tuberculosis in live animals. Virulence 18 21178505
1999 Abundance of NKT cells in the salivary glands but absence thereof in the liver and thymus of aly/aly mice with Sjögren syndrome. Cellular immunology 18 10087183
2014 Mitochondrial APE1/Ref-1 suppressed protein kinase C-induced mitochondrial dysfunction in mouse endothelial cells. Mitochondrion 17 24861944
2012 Accumulation of p100, a precursor of NF-κB2, enhances osteoblastic differentiation in vitro and bone formation in vivo in aly/aly mice. Molecular endocrinology (Baltimore, Md.) 17 22282470

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