Affinage

ALYREF

THO complex subunit 4 · UniProt Q86V81

Length
257 aa
Mass
26.9 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALYREF is a multifunctional nuclear RNA-binding protein that serves as a key mRNA export adaptor within the TREX complex and as a reader of 5-methylcytosine (m5C) in mRNA. As an export adaptor, ALYREF is recruited to spliced mRNPs by UAP56 in an ATP-dependent manner, bridges the THO complex and cap-binding machinery via its conserved WxHD motif, and hands off mRNA to the TAP/NXF1 export receptor—a transfer facilitated by arginine methylation that reduces ALYREF's RNA-binding affinity (PMID:11014198, PMID:11675789, PMID:20844015, PMID:26773052, PMID:20129943). ALYREF competes with the exosome cofactor hMTR4 for ARS2 binding at the cap-binding complex, thereby acting as a checkpoint that routes transcripts toward export rather than nuclear degradation (PMID:28801509). As an m5C reader, ALYREF recognizes NSUN2-deposited m5C marks to promote nuclear export and cytoplasmic stabilization of specific mRNAs including PKM2, EGFR, and JunD (PMID:28418038, PMID:33991457, PMID:38164181, PMID:38402198). ALYREF additionally functions as a transcriptional coactivator—originally identified through its interaction with LEF-1 and AML-1 at the TCRα enhancer—and can stabilize nuclear RNAs independently of export by protecting poly(A) tails from deadenylation (PMID:9119228, PMID:22290432).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1997 High

    Before ALYREF's RNA export role was known, it was identified as a transcriptional coactivator that enhances DNA binding by LEF-1 and AML-1, establishing that this protein functions at the level of transcriptional regulation at the TCRα enhancer.

    Evidence Yeast two-hybrid, co-IP, reporter assays, and antisense knockdown in T cells

    PMID:9119228

    Open questions at the time
    • Whether coactivator function is independent of later-discovered RNA export role
    • Structural basis for LEF-1/AML-1 interaction unknown
    • Genome-wide scope of transcriptional targets unresolved
  2. 2000 High

    The discovery that Aly/ALYREF is recruited to mRNP complexes in a splicing-dependent manner and promotes nuclear mRNA export redefined the protein as a central mRNA export adaptor, linking splicing to export.

    Evidence Co-IP, mRNA export assays in Xenopus oocytes, nuclear/cytoplasmic fractionation

    PMID:11014198

    Open questions at the time
    • Mechanism of splicing-dependent recruitment unresolved
    • Whether ALYREF is essential or redundant for bulk export unclear
  3. 2001 High

    Identification of UAP56 as the DEAD-box helicase that directly recruits ALYREF to mRNPs answered how ALYREF is loaded onto transcripts and established the first step of the TREX assembly pathway.

    Evidence Direct pulldown, co-IP, dominant-negative overexpression, UV cross-linking in Xenopus oocytes

    PMID:11675789

    Open questions at the time
    • ATP-dependent mechanism of loading not yet resolved
    • Whether UAP56 recruitment of ALYREF occurs on intronless mRNAs unknown
  4. 2002 High

    Demonstration that ALYREF is individually dispensable for bulk mRNA export in Drosophila (and later in C. elegans) revealed that redundant export adaptors exist, tempering the view of ALYREF as the sole essential export factor.

    Evidence RNAi knockdown in Drosophila S2 cells and C. elegans with poly(A)+ FISH

    PMID:12438415 PMID:12810921

    Open questions at the time
    • Identity of all redundant adaptors not defined
    • Whether ALYREF is essential for specific transcript classes rather than bulk export
  5. 2007 High

    Reconstitution of UAP56-mediated, ATP-dependent loading of ALYREF onto intronless RNA explained how ALYREF can function on transcripts that bypass splicing, with ATP hydrolysis triggering UAP56 release and ALYREF deposition.

    Evidence In vitro RNA-binding and ATPase assays with recombinant proteins, Xenopus oocyte validation

    PMID:17984224

    Open questions at the time
    • Structural basis of the UAP56–ALYREF–RNA ternary complex unknown
    • In vivo stoichiometry on intronless mRNAs not determined
  6. 2009 High

    Discovery that ALYREF and Thoc5 co-occupy TAP/NXF1 at non-overlapping sites, and that UIF acts as a parallel adaptor recruited via FACT, established the combinatorial logic of export adaptor engagement on a single mRNP.

    Evidence In vitro binding, co-IP, siRNA knockdown with transcript-specific and poly(A)+ FISH readouts

    PMID:19165146 PMID:19836239

    Open questions at the time
    • Rules governing which transcripts require ALYREF versus UIF unclear
    • Whether ALYREF and UIF compete or cooperate on the same molecule unresolved
  7. 2010 High

    Reconstitution of the TREX complex showed that UAP56 bridges ALYREF and CIP29 in an ATP-dependent trimeric complex associated with the THO complex, and that arginine methylation of ALYREF facilitates handover of mRNA to TAP/NXF1 by reducing RNA affinity.

    Evidence Recombinant protein reconstitution, proteomic immunopurification, mass spectrometry of methylation sites, in vitro and in vivo RNA-binding assays

    PMID:20129943 PMID:20844015

    Open questions at the time
    • Enzymes responsible for ALYREF arginine methylation not identified
    • Kinetic parameters of methylation-dependent handover not measured
  8. 2012 High

    Functional dissection showed that ALYREF and THO mutually depend on each other for mRNA binding and TREX integrity, and that ALYREF can stabilize nuclear RNA independently of export by protecting poly(A) tails from deadenylation—separating its stability and export functions.

    Evidence Systematic co-IP and siRNA of TREX components; tethering assay of ALYREF to KSHV PAN RNA with RNA half-life and poly(A) tail measurements

    PMID:22290432 PMID:23222130

    Open questions at the time
    • Deadenylase(s) antagonized by ALYREF not identified
    • Whether poly(A) stabilization is relevant for host mRNAs or only viral RNA
  9. 2016 High

    Identification of the conserved WxHD motif as the interface for ALYREF's interactions with eIF4A3 (EJC) and CBP80 (CBC) revealed how ALYREF integrates splicing-dependent and cap-dependent signals for mRNA export.

    Evidence Mutagenesis of WxHD motif, co-IP, in vitro splicing, nuclear speckle localization, mRNA export reporter assays

    PMID:26773052

    Open questions at the time
    • Atomic structure of WxHD–eIF4A3/CBP80 interface not available
    • Whether WxHD motif is required on all or a subset of mRNAs
  10. 2017 High

    The discovery that ALYREF is a specific m5C reader—binding NSUN2-deposited m5C marks to promote mRNA nuclear export—and that ALYREF competes with hMTR4 for ARS2 to decide RNA fate (export versus degradation) established a second major function for ALYREF beyond its TREX adaptor role.

    Evidence In vitro and in vivo m5C binding assays, RIP-seq, bisulfite sequencing, NSUN2 rescue, competition binding of ALYREF versus hMTR4 for ARS2

    PMID:28418038 PMID:28801509

    Open questions at the time
    • Structural basis for m5C recognition by ALYREF unknown
    • Relative contribution of m5C reading versus TREX-mediated export for individual transcripts not quantified
  11. 2021 Medium

    Multiple studies extended ALYREF's m5C reader and mRNA stabilization activities to oncogenic contexts, showing that ALYREF stabilizes MYC, PKM2, and MYCN-target mRNAs, and forms a coactivator complex with MYCN to drive USP3 transcription, establishing ALYREF as a cancer-relevant gene.

    Evidence CLIP/RIP for direct mRNA binding, ChIP for promoter occupancy, ubiquitination assays, transgenic neuroblastoma mouse models, GBM and bladder cancer functional studies

    PMID:33447056 PMID:33767157 PMID:33991457

    Open questions at the time
    • Whether ALYREF's oncogenic roles are mediated primarily through m5C reading or general export is unclear
    • No patient genetic data linking ALYREF mutations to cancer susceptibility
    • Most findings from single labs without independent replication
  12. 2024 Medium

    Recent work broadened the scope of ALYREF's m5C reader activity to additional target mRNAs (EGFR, JunD, RABL6, TK1) and showed it can promote mRNA splicing and stabilization, not just export, in an m5C-dependent manner, while also cooperating with m6A readers like hnRNPA2B1 for selective nuclear export.

    Evidence RIP at m5C sites, transcriptome-wide bisulfite sequencing, mRNA stability assays, organoid and xenograft models, co-IP of hnRNPA2B1–ALYREF–NXF1

    PMID:36806253 PMID:38164181 PMID:38402198 PMID:38626369

    Open questions at the time
    • How ALYREF distinguishes m5C sites for export versus stabilization versus splicing is unknown
    • Cross-talk between m5C and m6A reading by ALYREF-containing complexes is poorly defined
    • Many target-specific claims lack independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis by which ALYREF recognizes m5C, the rules governing whether ALYREF promotes export versus stability versus splicing of a given transcript, and whether its transcriptional coactivator function is mechanistically separable from its RNA export adaptor role remain unresolved.
  • No crystal or cryo-EM structure of ALYREF bound to m5C-containing RNA
  • No genome-wide quantitative partitioning of ALYREF's export versus stability versus transcriptional functions
  • Relative physiological importance of redundant export adaptors in mammalian cells undefined

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
Localization
GO:0005634 nucleus 4 GO:0005654 nucleoplasm 1
Pathway
R-HSA-8953854 Metabolism of RNA 9 R-HSA-9609507 Protein localization 5 R-HSA-74160 Gene expression (Transcription) 2
Partners
ARS2CBP80EIF4A3NSUN2NXF1THOC2THOC5UAP56
Complex memberships
CBC-ARS2 complexTREX complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Aly (ALYREF), the metazoan homologue of yeast mRNA export factor Yra1p, is recruited to mRNP complexes in a splicing-dependent manner and promotes nuclear mRNA export; it associates with spliced mRNPs but not with pre-assembled mRNPs lacking introns or hnRNP complexes, and shuttles between nucleus and cytoplasm. Co-immunoprecipitation, in vivo mRNA export assays in Xenopus oocytes, nuclear/cytoplasmic fractionation, immunofluorescence co-localization with splicing factors Nature High 11014198
2001 The DEAD-box helicase UAP56 directly and specifically interacts with Aly/ALYREF, recruits it to the spliced mRNP, and this interaction is required for Aly recruitment to spliced mRNA; excess UAP56 acts as a dominant-negative inhibitor of mRNA export by blocking Aly recruitment. Direct pulldown, co-immunoprecipitation, dominant-negative overexpression in Xenopus oocytes, UV cross-linking, mass spectrometry Nature High 11675789
2002 In Drosophila cells, REF1/Aly and other EJC proteins are individually dispensable for bulk mRNA export; only co-depletion of REF1 and RNPS1, or simultaneous depletion of all EJC proteins, causes partial nuclear accumulation of polyadenylated RNA, indicating redundant export adaptors exist. RNAi knockdown in Drosophila S2 cells, poly(A)+ RNA FISH to measure nuclear accumulation The Journal of cell biology High 12438415
2003 In C. elegans, simultaneous RNAi depletion of all three REF/Aly family members does not compromise viability, developmental progression, or mRNA export, demonstrating that REF/Aly proteins are dispensable for bulk mRNA export in this organism. RNAi knockdown of all three C. elegans REF genes individually and in combination; poly(A)+ RNA FISH RNA High 12810921
2007 UAP56 recruits Aly/REF onto intronless mRNAs in an ATP-dependent manner; ATP-bound UAP56 binds both RNA and Aly/REF simultaneously, stimulating UAP56 ATPase activity cooperatively, and upon ATP hydrolysis UAP56 dissociates, leaving Aly/REF loaded on the mRNA. In vitro RNA-binding assays, ATP hydrolysis assays, recombinant protein interaction studies, dominant-negative UAP56 injection in Xenopus oocytes Molecular and cellular biology High 17984224
2009 Aly/ALYREF and Thoc5 bind simultaneously to non-overlapping sites on the Tap-p15 export receptor; Thoc5 functions as a co-adaptor for nuclear export of HSP70 mRNA specifically, requiring both Thoc5 and Aly for this transcript class. Co-immunoprecipitation, in vitro binding assays, siRNA knockdown with specific mRNA export readout The EMBO journal High 19165146
2009 UIF (UAP56-interacting factor) is a novel mRNA export adaptor that works in parallel with REF/ALY; both REF and UIF are found on the same mRNA molecules, both are required for efficient mRNA export, and UIF is recruited to mRNA via the histone chaperone FACT (through its SSRP1 subunit), a mechanism distinct from REF's UAP56-dependent recruitment. Co-immunoprecipitation, siRNA knockdown, poly(A)+ RNA FISH, in vitro binding assays Current biology High 19836239
2010 UAP56 mediates an ATP-dependent interaction between the THO complex and both CIP29 and Aly, assembling the TREX complex in an ATP-dependent manner; recombinant UAP56, Aly, and CIP29 form an ATP-dependent trimeric complex in vitro, with UAP56 bridging CIP29 and Aly. Proteomic immunopurification of TREX, in vitro reconstitution with recombinant proteins expressed in E. coli, ATP-dependency assays Genes & development High 20844015
2010 Arginine methylation of REF/ALYREF within its TAP/NXF1-binding and RNA-binding domains reduces its RNA-binding affinity in vitro and in vivo, facilitating efficient displacement of RNA from REF by TAP/NXF1 for handover to the export receptor. Mass spectrometry mapping of methylation sites, in vitro RNA-binding assays with methylated/unmethylated REF, in vivo RNA-binding measurements Nucleic acids research High 20129943
2012 Aly and THO complex subunits (Thoc2 and Thoc5) directly interact, and both Aly and THO are required for assembly of the human TREX complex and for association of UAP56 with the spliced mRNA; Aly and THO mutually depend on each other for mRNA binding, and THO links UAP56 to the cap-binding protein CBP80. Co-immunoprecipitation, recombinant protein pulldown, siRNA knockdown of individual TREX components, mRNA export assays, spliced mRNA co-immunoprecipitation Nucleic acids research High 23222130
2016 A short conserved WxHD motif in an unstructured region of ALYREF is required for RNA binding and interaction with both eIF4A3 (EJC component) and CBP80 (cap-binding complex); mutation of this motif abolishes proper localization to nuclear speckles and export of a spliced reporter mRNA. In vitro splicing assays, computational motif analysis, mutagenesis of WxHD motif, co-immunoprecipitation, nuclear speckle localization by immunofluorescence, mRNA export reporter assays Nucleic acids research High 26773052
2017 ALYREF functions as an m5C reader that specifically recognizes 5-methylcytosine in mRNAs; NSUN2 is the methyltransferase that deposits m5C in mRNAs, and ALYREF binding to m5C promotes mRNA nuclear export. NSUN2 modulates ALYREF's nuclear-cytoplasmic shuttling and RNA-binding affinity; export defects upon NSUN2 depletion are rescued by wild-type but not methyltransferase-defective NSUN2. In vitro and in vivo binding assays (m5C-containing vs. unmodified RNA), RIP-seq, RNA bisulfite sequencing for m5C mapping, NSUN2 reconstitution experiments, nuclear/cytoplasmic fractionation, mRNA export assays Cell research High 28418038
2017 Exosome cofactor hMTR4 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. Co-immunoprecipitation, competition binding assays between hMTR4 and ALYREF for ARS2, RNA-seq of exosome targets, knockdown experiments The EMBO journal High 28801509
2012 REF/Aly can stabilize nuclear RNAs independently of their export; tethering REF/Aly to the KSHV PAN RNA increases its nuclear abundance and half-life but is not sufficient for export, and REF/Aly protects the poly(A) tail from deadenylation. Viral ORF57-mediated recruitment, tethering assay of REF/Aly to PAN RNA, RNA half-life measurement, poly(A) tail analysis Molecular and cellular biology High 22290432
2005 HSV-1 ICP27 recruits Aly/REF to viral transcription sites through direct interaction requiring ICP27 residues in a specific region; however, TAP/NXF1 is required for ICP27 export to the cytoplasm and does not require Aly/REF as a bridge, as ICP27 interacts directly with TAP/NXF1 via its C-terminus. Co-immunoprecipitation, colocalization immunofluorescence, ICP27 deletion/point mutants, siRNA-knockdown functional studies Journal of virology Medium 15767397
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's effects on the malignant phenotype and for USP3's effect on MYCN stability. Co-immunoprecipitation demonstrating ALYREF-MYCN complex, ChIP/transcription assays for USP3, ubiquitination assays, transgenic neuroblastoma mouse models, in vitro and in vivo functional studies Nature communications High 33767157
2022 ALYREF binds to the NEAT1 promoter region to enhance global NEAT1 transcriptional activity and also stabilizes CPSF6, a protein that selectively promotes generation of the short NEAT1 isoform post-transcriptionally; ALYREF additionally directly binds and stabilizes the short NEAT1 isoform. ChIP assay for NEAT1 promoter binding, CPSF6 co-immunoprecipitation, RNA-binding and stability assays, gene expression profiling, orthotopic mouse models Cellular and molecular life sciences Medium 35776213
2021 ALYREF stabilizes PKM2 mRNA by binding to its m5C sites in the 3'-UTR, promoting bladder cancer cell proliferation through PKM2-mediated glycolysis; HIF-1α indirectly upregulates PKM2 by activating ALYREF transcription. RNA immunoprecipitation (RIP), RNA-sequencing, dual-luciferase reporter assays, Western blotting, in vitro and in vivo functional studies Cancer communications Medium 33991457
2023 ALYREF specifically binds to hypermethylated m5C sites in RABL6 and TK1 mRNAs via its K171 domain, promoting their splicing and stabilization; ALYREF also recognizes hypermethylated m5C sites in NSUN2 mRNA, creating a positive feedback loop upregulating NSUN2 in bladder cancer. Transcriptome-wide RNA bisulfite sequencing (BisSeq), RNA-seq, RIP-seq, patient-derived organoids, orthotopic xenograft mouse model Cell death & disease Medium 36806253
2024 ALYREF directly binds m5C modification sites in the EGFR 3'-UTR to stabilize EGFR mRNA, promoting LIHC cell proliferation and invasion through EGFR-STAT3 signaling pathway activation. RIP demonstrating ALYREF binding to m5C sites in EGFR 3'-UTR, mRNA stability assays, in vitro and in vivo functional studies, 3 independent LIHC cohorts International journal of biological sciences Medium 38164181
2020 ALYREF m5C reader function promotes murine leukemia virus (MLV) replication; m5C is highly enriched in MLV genomic RNA, and ALYREF plays an important role in regulating MLV replication. Mass spectrometry and bisulfite sequencing for m5C mapping in viral RNA, ALYREF functional knockdown with viral replication readout Journal of virology Medium 32321818
2019 In Drosophila, downregulation of Ref1 (fly orthologue of ALYREF) mitigates TDP-43-induced toxicity and also reduces toxicity from C9orf72 GGGGCC repeat expansion; Ref1 depletion lowered mRNA levels of TDP-43 and C9orf72 transgenes but not an unrelated control, suggesting ALYREF promotes export/stability of these disease-associated mRNAs. Unbiased genetic screen in Drosophila, RNAi knockdown, qRT-PCR for mRNA levels, toxicity phenotypic readout Acta neuropathologica communications Medium 31036086
1997 ALY (ALYREF) is a context-dependent transcriptional coactivator that specifically associates with the activation domains of LEF-1 and AML-1, increases DNA binding by both transcription factors, and is required for TCRα enhancer activity in T cells; anti-sense oligonucleotide knockdown of ALY virtually eliminates TCRα enhancer activity. Yeast two-hybrid cloning, co-immunoprecipitation, DNA binding assays, transient transfection reporter assays in HeLa and T cells, anti-sense oligonucleotide knockdown Genes & development High 9119228
2021 ALYREF drives GBM cell proliferation by binding to and stabilizing MYC mRNA; MYC transcriptionally regulates ALYREF expression, creating a positive feedback loop; ALYREF activates the Wnt/β-catenin signaling pathway downstream. CLIP assay showing ALYREF-MYC mRNA binding, RNA stability assays, ChIP assay for MYC binding to ALYREF promoter, in vitro and in vivo tumor formation assays OncoTargets and therapy Medium 33447056
2022 ALYREF recognizes m5C-modified YBX2 and SMO mRNAs and exports them from nucleus to cytoplasm, increasing YBX2 and SMO protein expression, thereby inhibiting adipogenesis and promoting myogenesis respectively. RNA bisulfite sequencing for m5C profiling, RIP demonstrating ALYREF binding to m5C-modified mRNAs, nuclear/cytoplasmic fractionation, in vitro differentiation assays Cellular and molecular life sciences Medium 35962235
2024 ALYREF specifically recognizes m5C sites in JunD mRNA, maintains JunD mRNA stabilization, and subsequently upregulates SLC7A5 transcription; the ALYREF-JunD-SLC7A5 axis depletes amino acids in the tumor microenvironment, restricting CD8+ T cell function. RIP for ALYREF-JunD mRNA binding at m5C sites, mRNA stability assays, ChIP/transcription assays, in vivo tumor growth with immune depletion experiments Cell death discovery Medium 38402198
2023 LINC02159 lncRNA binds to ALYREF to enhance stabilization of YAP1 mRNA via m5C modification, leading to overexpression of YAP1 and activation of Hippo and β-catenin signaling pathways in NSCLC cells. RNA pulldown/RIP demonstrating LINC02159-ALYREF interaction, mRNA stability assays for YAP1, transcriptomic analysis, rescue experiments in NSCLC cells Molecular cancer Medium 37537569
2024 ISGylated hnRNPA2B1 (as m6A reader) mediates selective nuclear export of m6A-tagged mRNAs via the ALYREF/NXF1 complex, promoting stemness-related gene expression in breast cancer cells. Co-immunoprecipitation of hnRNPA2B1 with ALYREF and NXF1, mRNA export assays, nuclear/cytoplasmic fractionation, siRNA knockdown experiments Advanced science Medium 38626369

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 854 28418038
2000 Going APE over ref-1. Mutation research 478 11018583
1996 The redox/DNA repair protein, Ref-1, is essential for early embryonic development in mice. Proceedings of the National Academy of Sciences of the United States of America 425 8799128
1997 Identification of redox/repair protein Ref-1 as a potent activator of p53. Genes & development 423 9119221
2000 The protein Aly links pre-messenger-RNA splicing to nuclear export in metazoans. Nature 418 11014198
2009 The many functions of APE1/Ref-1: not only a DNA repair enzyme. Antioxidants & redox signaling 409 18976116
2001 Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly. Nature 330 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 276 8299692
1997 ALY, a context-dependent coactivator of LEF-1 and AML-1, is required for TCRalpha enhancer function. Genes & development 255 9119228
2021 The role of the HIF-1α/ALYREF/PKM2 axis in glycolysis and tumorigenesis of bladder cancer. Cancer communications (London, England) 246 33991457
2009 Transcriptional regulatory functions of mammalian AP-endonuclease (APE1/Ref-1), an essential multifunctional protein. Antioxidants & redox signaling 215 18715144
1999 Ref-1 regulates the transactivation and pro-apoptotic functions of p53 in vivo. The EMBO journal 201 10523305
2011 p62, Ref(2)P and ubiquitinated proteins are conserved markers of neuronal aging, aggregate formation and progressive autophagic defects. Autophagy 181 21325881
2002 REF1/Aly and the additional exon junction complex proteins are dispensable for nuclear mRNA export. The Journal of cell biology 168 12438415
1997 On the key role of secondary lymphoid organs in antiviral immune responses studied in alymphoplastic (aly/aly) and spleenless (Hox11(-)/-) mutant mice. The Journal of experimental medicine 150 9182687
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
2000 Abnormal immune function of hemopoietic cells from alymphoplasia (aly) mice, a natural strain with mutant NF-kappa B-inducing kinase. Journal of immunology (Baltimore, Md. : 1950) 133 10878354
2009 UIF, a New mRNA export adaptor that works together with REF/ALY, requires FACT for recruitment to mRNA. Current biology : CB 121 19836239
2017 Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic. NPJ precision oncology 119 28825044
2001 BeF(3)(-) acts as a phosphate analog in proteins phosphorylated on aspartate: structure of a BeF(3)(-) complex with phosphoserine phosphatase. Proceedings of the National Academy of Sciences of the United States of America 119 11438683
2009 Adaptor Aly and co-adaptor Thoc5 function in the Tap-p15-mediated nuclear export of HSP70 mRNA. The EMBO journal 117 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 113 23222130
2005 The multifunctional DNA repair/redox enzyme Ape1/Ref-1 promotes survival of neurons after oxidative stress. DNA repair 108 15661660
2011 Impact of APE1/Ref-1 redox inhibition on pancreatic tumor growth. Molecular cancer therapeutics 98 21700832
2008 Small-molecule inhibitor of the AP endonuclease 1/REF-1 E3330 inhibits pancreatic cancer cell growth and migration. Molecular cancer therapeutics 97 18645011
2007 ATP-dependent recruitment of export factor Aly/REF onto intronless mRNAs by RNA helicase UAP56. Molecular and cellular biology 97 17984224
1999 Phosphorylation of the DNA repair protein APE/REF-1 by CKII affects redox regulation of AP-1. Oncogene 94 10023679
2017 Exosome cofactor hMTR4 competes with export adaptor ALYREF to ensure balanced nuclear RNA pools for degradation and export. The EMBO journal 93 28801509
2003 The Ref/Aly proteins are dispensable for mRNA export and development in Caenorhabditis elegans. RNA (New York, N.Y.) 90 12810921
2009 Genome-wide analysis and proteomic studies reveal APE1/Ref-1 multifunctional role in mammalian cells. Proteomics 86 19180539
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 84 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 80 36806253
1998 Ref-1 controls pax-8 DNA-binding activity. Biochemical and biophysical research communications 80 9813166
2016 A short conserved motif in ALYREF directs cap- and EJC-dependent assembly of export complexes on spliced mRNAs. Nucleic acids research 78 26773052
1997 The DNA repair activity of human redox/repair protein APE/Ref-1 is inactivated by phosphorylation. Cancer research 78 9407949
2023 LINC02159 promotes non-small cell lung cancer progression via ALYREF/YAP1 signaling. Molecular cancer 75 37537569
2003 APE/Ref-1 and the mammalian response to genotoxic stress. Toxicology 75 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
2003 Oxidative stress stimulates IL-4 and IL-6 production in mast cells by an APE/Ref-1-dependent pathway. European journal of immunology 70 12884291
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 64 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 64 24942738
2000 Human APE/Ref-1 protein. The international journal of biochemistry & cell biology 62 11084372
2009 Downregulation of APE1/Ref-1 is involved in the senescence of mesenchymal stem cells. Stem cells (Dayton, Ohio) 60 19492297
1994 Development of intestinal intraepithelial T lymphocytes is independent of Peyer's patches and lymph nodes in aly mutant mice. Journal of immunology (Baltimore, Md. : 1950) 59 8051406
2020 Revascularization and limb salvage following critical limb ischemia by nanoceria-induced Ref-1/APE1-dependent angiogenesis. Biomaterials 58 32146371
2016 APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury. Proceedings of the National Academy of Sciences of the United States of America 54 27274063
2010 Arginine methylation of REF/ALY promotes efficient handover of mRNA to TAP/NXF1. Nucleic acids research 54 20129943
2022 APE1/Ref-1 Role in Inflammation and Immune Response. Frontiers in immunology 52 35296074
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
1996 Defects of somatic hypermutation and class switching in alymphoplasia (aly) mutant mice. International immunology 49 8757952
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
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
2018 Blocking HIF signaling via novel inhibitors of CA9 and APE1/Ref-1 dramatically affects pancreatic cancer cell survival. Scientific reports 44 30214007
2016 Urinary APE1/Ref-1: A Potential Bladder Cancer Biomarker. Disease markers 44 27057081
2007 Notch-GATA synergy promotes endoderm-specific expression of ref-1 in C. elegans. Development (Cambridge, England) 44 18003741
2019 Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration. Redox biology 43 30802716
2017 Inhibitors of nuclease and redox activity of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1). Bioorganic & medicinal chemistry 43 28161249
2024 ALYREF-mediated RNA 5-Methylcytosine modification Promotes Hepatocellular Carcinoma Progression Via Stabilizing EGFR mRNA and pSTAT3 activation. International journal of biological sciences 41 38164181
2014 Monitoring autophagic flux using Ref(2)P, the Drosophila p62 ortholog. Cold Spring Harbor protocols 41 25183816
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
2007 Bilirubin-induced cell toxicity involves PTEN activation through an APE1/Ref-1-dependent pathway. Journal of molecular medicine (Berlin, Germany) 40 17479230
2007 Redox activation of Ref-1 potentiates cell survival following myocardial ischemia reperfusion injury. Free radical biology & medicine 40 17602955
2016 Dynamic Regulation of APE1/Ref-1 as a Therapeutic Target Protein. Chonnam medical journal 39 27231670
2002 The zinc finger protein REF-2 functions with the Hox genes to inhibit cell fusion in the ventral epidermis of C. elegans. Development (Cambridge, England) 38 12091304
1997 Increase in Ref-1 mRNA and protein by thyrotropin in rat thyroid FRTL-5 cells. Biochemical and biophysical research communications 38 9223428
2007 Differential expression pattern of rubber elongation factor (REF) mRNA transcripts from high and low yielding clones of rubber tree (Hevea brasiliensis Muell. Arg.). Plant cell reports 37 17632724
2023 ALYREF (Aly/REF export factor): A potential biomarker for predicting cancer occurrence and therapeutic efficacy. Life sciences 36 38135116
2012 Viral factors reveal a role for REF/Aly in nuclear RNA stability. Molecular and cellular biology 36 22290432
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 35 35962235
2021 APE1/Ref-1 - One Target with Multiple Indications: Emerging Aspects and New Directions. Journal of cellular signaling 35 34557865
2024 HnRNPA2B1 ISGylation Regulates m6A-Tagged mRNA Selective Export via ALYREF/NXF1 Complex to Foster Breast Cancer Development. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 34 38626369
1997 The structure and functions of the HAP1/Ref-1 protein. Oncology research 34 9406232
2019 Antitumor Activity and Mechanistic Characterization of APE1/Ref-1 Inhibitors in Bladder Cancer. Molecular cancer therapeutics 33 31413178
2009 Arginine methylation of the ICP27 RGG box regulates the functional interactions of ICP27 with SRPK1 and Aly/REF during herpes simplex virus 1 infection. Journal of virology 31 19553338
2012 DNA Repair and Cancer Therapy: Targeting APE1/Ref-1 Using Dietary Agents. Journal of oncology 29 22997517
2017 APE1/Ref-1 Inhibits Phosphate-Induced Calcification and Osteoblastic Phenotype Changes in Vascular Smooth Muscle Cells. International journal of molecular sciences 25 28946662
2014 Suppression of choroidal neovascularization through inhibition of APE1/Ref-1 redox activity. Investigative ophthalmology & visual science 24 24970265
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 24 23637401
1996 Cloning, sequencing and overexpression in Escherichia coli of the alginatelyase-encoding aly gene of Pseudomonas alginovora: identification of three classes of alginate lyases. The Biochemical journal 24 8912697
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
2013 Homologous Hevea brasiliensis REF (Hevb1) and SRPP (Hevb3) present different auto-assembling. Biochimica et biophysica acta 23 24239687
2024 New Ref-1/APE1 targeted inhibitors demonstrating improved potency for clinical applications in multiple cancer types. Pharmacological research 22 38311014
2024 ALYREF-JunD-SLC7A5 axis promotes pancreatic ductal adenocarcinoma progression through epitranscriptome-metabolism reprogramming and immune evasion. Cell death discovery 22 38402198
1995 Ref-1 expression in adult mammalian neurons and astrocytes. Neuroscience letters 22 7644143
2022 Pharmacological inhibition of Ref-1 enhances the therapeutic sensitivity of papillary thyroid carcinoma to vemurafenib. Cell death & disease 21 35136031
2021 Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy. International journal of molecular sciences 21 34638620
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
2024 The APE1/REF-1 and the hallmarks of cancer. Molecular biology reports 20 38165468
2021 Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours. British journal of cancer 20 33658640
2019 Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies. Acta neuropathologica communications 20 31036086