Affinage

HNRNPA1

Heterogeneous nuclear ribonucleoprotein A1 · UniProt P09651

Length
372 aa
Mass
38.7 kDa
Annotated
2026-04-28
100 papers in source corpus 43 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

hnRNP A1 is a multifunctional RNA- and DNA-binding protein that acts as a major regulator of alternative splicing, telomere maintenance, miRNA biogenesis, and IRES-dependent translation. Its two N-terminal RRMs form an antiparallel bipartite RNA-binding domain that binds high-affinity splicing silencer elements and then spreads cooperatively along RNA to antagonize SR protein binding and repress exon inclusion, while also allosterically remodeling pri-miRNA terminal loops to promote (pri-miR-18a) or inhibit (pri-let-7a) Drosha processing (PMID:11779509, PMID:29946118, PMID:20639884). At telomeres, hnRNP A1 unfolds G-quadruplex structures via synergistic action of UP1 and its RGG-box and displaces RPA from single-stranded telomeric DNA in a TERRA-regulated manner to facilitate the RPA-to-POT1 switch and modulate telomerase access (PMID:16603717, PMID:21399625, PMID:30247678). Nucleo-cytoplasmic shuttling is governed by the M9/PY-NLS in the glycine-rich C-terminal domain and is regulated by an integrated network of post-translational modifications—including p38-mediated phosphorylation, S6K2-mediated phosphorylation, PRMT-mediated arginine methylation, SIRT1/6-mediated deacetylation, TRAF6-mediated ubiquitination, and O-GlcNAcylation—that couple signaling inputs to splicing, translation, and localization outputs; disease-associated mutations in the prion-like domain accelerate amyloid fibril formation nucleated at condensate interfaces, with the PY-NLS itself forming the fibril core (PMID:10769024, PMID:25324306, PMID:23455423, PMID:33311513, PMID:37749234).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 High

    The mechanism by which hnRNP A1 is targeted to the nucleus was unknown; identification of the M9 domain as a novel non-classical NLS sufficient for nuclear import, combined with evidence that export requires an RRM and re-import depends on nuclear transcription, established that hnRNP A1 shuttles via a dedicated transport pathway coupled to mRNA metabolism.

    Evidence Fusion protein localization assays with domain deletions/swaps in transfected cells; WGA pore blockade; pronuclear transplantation in mouse embryos

    PMID:11282028 PMID:7730395 PMID:7769000

    Open questions at the time
    • Identity of the M9/PY-NLS import receptor (transportin/Kap-β2) was not yet defined in these studies
    • Specific phosphorylation sites regulating shuttling were unknown
  2. 1997 High

    The structural basis for RNA recognition by hnRNP A1 was undefined; crystal structures of the UP1 fragment revealed two independently folded RRMs arranged antiparallel via inter-domain ion pairs, forming a single bipartite RNA-binding surface, and subsequent NMR confirmed this orientation persists in solution.

    Evidence X-ray crystallography at 1.75–1.9 Å (two independent groups); NMR with segmental isotope labeling

    PMID:23247503 PMID:9115444 PMID:9164463

    Open questions at the time
    • RNA-bound structure of full-length tandem RRMs was not available until later NMR studies
    • Contribution of the C-terminal glycine-rich domain to RNA binding was not addressed
  3. 1999 High

    How hnRNP A1 recognizes telomeric DNA was structurally undefined; a crystal structure of UP1 bound to telomeric ssDNA revealed a UP1 dimer engaging two antiparallel DNA strands through inter-subunit RRM contacts, providing the first structural model for telomeric DNA recognition.

    Evidence X-ray crystallography at 2.1 Å resolution

    PMID:10323862

    Open questions at the time
    • G-quadruplex unwinding mechanism was not yet addressed
    • Role of the RGG-box in telomeric DNA binding was unknown
  4. 2001 High

    The mechanism by which hnRNP A1 achieves splicing silencing was unclear; reconstitution experiments showed that hnRNP A1 first binds a high-affinity ESS site, then cooperatively spreads along the pre-mRNA to block U2 snRNP association at the branch point, with this spreading antagonized by SR protein SF2/ASF.

    Evidence In vitro splicing reconstitution; depletion/add-back; UV cross-linking; cooperative spreading assays with HIV-1 pre-mRNA substrates

    PMID:11598017 PMID:11779509 PMID:12458794 PMID:19667073

    Open questions at the time
    • Whether cooperative spreading occurs genome-wide or only on specific substrates was unknown
    • Structural basis of hnRNP A1 oligomerization on RNA was not resolved
  5. 2000 High

    The signaling pathway controlling hnRNP A1 subcellular localization was unknown; p38-MAPK was identified as necessary and sufficient for stress-induced cytoplasmic accumulation of hnRNP A1, directly linking signal transduction to alternative splicing regulation.

    Evidence Pharmacological activation/inhibition of MKK3/6–p38; immunofluorescence; in vivo splicing reporters

    PMID:10769024

    Open questions at the time
    • Specific phosphorylation sites on hnRNP A1 targeted by p38 were not mapped
    • Whether p38-mediated relocalization affects telomere or miRNA functions was untested
  6. 2006 High

    Whether hnRNP A1 directly participates in telomere biology was unresolved; depletion/reconstitution showed hnRNP A1 is required for telomerase activity in cell extracts, unwinds G-quadruplex structures, and occupies telomeres in vivo by ChIP.

    Evidence In vitro telomerase assay with depletion/add-back; G-quadruplex unwinding; ChIP

    PMID:16603717

    Open questions at the time
    • How hnRNP A1 coordinates with POT1 and RPA at telomeres was unknown
    • Contribution of the RGG-box domain to G-quadruplex unfolding was not dissected
  7. 2011 High

    How telomeric ssDNA transitions from RPA to POT1 protection was mechanistically obscure; reconstitution with purified proteins demonstrated that hnRNP A1 displaces RPA from telomeric ssDNA, and TERRA acts as a cell-cycle-dependent timer—inhibiting displacement in early S phase and later removing hnRNP A1 to permit POT1 loading.

    Evidence In vitro competition assays with purified hnRNPA1, RPA, POT1, and TERRA; cell extract fractionation

    PMID:21399625 PMID:23935072

    Open questions at the time
    • In vivo validation of the three-state switch model was not provided
    • Whether TERRA regulation of hnRNP A1 involves direct sequestration versus conformational change was not distinguished
  8. 2010 High

    Whether hnRNP A1 influences miRNA biogenesis was unknown; it was shown to bind the terminal loop of pri-let-7a-1 to inhibit Drosha processing (competing with KSRP), and separately to bind the pri-miR-18a terminal loop to allosterically destabilize stem base-pairing and promote Microprocessor cleavage.

    Evidence In vitro Drosha processing assay; NMR/SAXS structure of hnRNPA1–pri-miR-18a complex; EMSA; mutagenesis

    PMID:20639884 PMID:29946118

    Open questions at the time
    • The full scope of miRNAs regulated by hnRNP A1 terminal loop binding was not determined
    • Whether post-translational modifications modulate miRNA-related functions was untested
  9. 2013 High

    How disease mutations in the prion-like domain cause pathology was mechanistically unclear; D262N and N267S mutations were shown to strengthen steric zipper motifs, accelerating self-seeding amyloid fibril formation and promoting excess stress granule incorporation.

    Evidence In vitro fibril formation with thioflavin T fluorescence; EM; Drosophila and cell models

    PMID:23455423

    Open questions at the time
    • Whether fibrils form in patient tissue was not demonstrated at atomic resolution
    • The reversibility of mutant fibril formation was not addressed
  10. 2014 High

    How hnRNP A1 couples anti-apoptotic mRNA export to IRES-dependent translation was unknown; S6K2-mediated phosphorylation at Ser4/6 was shown to promote hnRNP A1 binding to BCL-XL/XIAP mRNAs and their nuclear export, with cytoplasmic dissociation de-repressing their IRES translation, followed by sumoylation-dependent nuclear re-import.

    Evidence In vitro kinase assay; RNA-IP; nuclear/cytoplasmic fractionation; S4/6A mutant; sumoylation assay

    PMID:25324306

    Open questions at the time
    • Whether S6K2 phosphorylation affects splicing or telomere functions was not examined
    • The 14-3-3 binding mechanism and its contribution to sumoylation were not structurally defined
  11. 2016 High

    The post-translational modification landscape regulating hnRNP A1 localization and splicing expanded with identification of O-GlcNAcylation promoting transportin1 interaction/nuclear import, and TRAF6-mediated ubiquitination modulating alternative splicing of Arhgap1 in hematopoiesis.

    Evidence Mass spectrometry PTM mapping; co-IP; nuclear/cytoplasmic fractionation; global ubiquitin proteomics with splicing and Cdc42 activity assays

    PMID:27913144 PMID:28024152

    Open questions at the time
    • Crosstalk between O-GlcNAcylation, phosphorylation, and ubiquitination on the same hnRNP A1 molecule was not dissected
    • In vivo hematopoietic phenotypes of hnRNP A1 ubiquitination-deficient mutants were not characterized
  12. 2017 High

    How arginine methylation modulates hnRNP A1 function was incompletely understood; PRMT5-mediated symmetric dimethylation at R218/R225 was shown to enhance IRES RNA interaction and promote Cyclin D1/c-Myc IRES translation, and NMR structures revealed the precise binding mode of RRM2-upstream/RRM1-downstream on the ISS-N1 splicing silencer controlling SMN exon 7.

    Evidence In vitro methylation; mass spectrometry; IRES reporter; NMR structure; in-cell splicing assay; mutagenesis

    PMID:28115626 PMID:28650318

    Open questions at the time
    • Whether PRMT5 methylation affects telomere or miRNA functions of hnRNP A1 was untested
    • Structural basis of methylation-enhanced IRES binding was not resolved
  13. 2019 High

    Whether metabolic signals regulate hnRNP A1 splicing activity was unclear; SIRT1/6-mediated deacetylation at four lysine residues upon glucose starvation was shown to shift PKM splicing from PKM2 to PKM1, reducing glycolysis in hepatocellular carcinoma cells.

    Evidence In vitro deacetylation assay; mass spectrometry acetylation site mapping; RT-PCR splicing assay; metabolic assays

    PMID:30858544

    Open questions at the time
    • Whether acetylation affects other hnRNP A1 functions (telomere, miRNA, IRES) was not examined
    • The acetyltransferase(s) responsible for basal hnRNP A1 acetylation were not identified
  14. 2020 High

    The structural basis for the dual role of the PY-NLS in both nuclear import and amyloid fibril formation was unknown; cryoEM of LC domain fibrils revealed that the PY-NLS/M9 domain forms the fibril core, with ALS/MSP disease mutations clustering within this core, explaining why transport-competent and fibril-competent conformations are mutually exclusive.

    Evidence Cryo-electron microscopy structure determination; mutagenesis

    PMID:33311513

    Open questions at the time
    • Whether Kap-β2/transportin binding can disaggregate preformed fibrils was not tested in this study
    • The fibril structure of full-length hnRNP A1 (including RRMs) was not determined
  15. 2023 High

    Where within condensates fibril nucleation initiates was unresolved; time-resolved imaging showed that hnRNPA1 LC domain fibrils form preferentially at the condensate interface rather than in the interior, and surfactant coating of the interface suppresses fibrillization.

    Evidence Time-resolved fluorescence microscopy; ThT amyloid assay; surfactant interface coating; confocal and TIRF microscopy

    PMID:37749234

    Open questions at the time
    • Whether the interface nucleation mechanism applies to full-length hnRNP A1 or in cellular stress granules was not shown
    • The molecular events at the interface that lower the nucleation barrier were not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: how the full repertoire of post-translational modifications is integrated on individual hnRNP A1 molecules to coordinate its splicing, telomere, miRNA, and translation functions in a context-dependent manner; whether condensate-interface-nucleated fibril formation occurs in disease-relevant cells; and what determines substrate selectivity among the hundreds of regulated alternative splicing events.
  • No integrative PTM code model exists
  • No in vivo imaging of fibril nucleation at condensate interfaces in neurons
  • Structural basis for cooperative spreading selectivity on different pre-mRNAs is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 9 GO:0003677 DNA binding 5 GO:0098772 molecular function regulator activity 5 GO:0140098 catalytic activity, acting on RNA 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 3 GO:0005829 cytosol 3
Pathway
R-HSA-8953854 Metabolism of RNA 10 R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 2
Partners
DDX5PRMT5RPS6KB2SIRT1SIRT6TNPO1TRAF6YWHAZ
Complex memberships
7SK snRNPhnRNP complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 A ~40 amino acid segment near the carboxyl terminus of hnRNP A1, designated M9, is necessary and sufficient for nuclear localization; attaching M9 to cytoplasmic proteins (beta-galactosidase, pyruvate kinase) completely relocalized them to the nucleus. M9 is a novel type of NLS distinct from classical basic-type NLS. Fusion protein localization assay in transfected cells; deletion/domain-swap analysis The Journal of cell biology High 7730395 7769000
1995 Nuclear export of hnRNP A1 requires at least one RNA-binding domain, consistent with the protein exiting the nucleus bound to mRNA. Nuclear re-import is carrier-mediated (blocked by WGA) and depends on the presence of nascent transcripts in the nucleus rather than RNA in the cytoplasm. Transfection of domain-deletion constructs fused to CAT reporter; WGA nuclear pore blockade; pronuclear transplantation in mouse embryos Journal of cell science High 11282028 7769000
1997 Crystal structure of hnRNP A1 UP1 (two RRMs) at 1.75–1.9 Å resolution reveals two independently folded RBDs connected by a flexible linker, oriented antiparallel and held by Arg-Asp ion pairs, creating an extended RNA-binding surface. The two RRMs function as a single bipartite domain. X-ray crystallography Nature structural biology / Structure High 9115444 9164463
1999 Crystal structure of UP1 complexed with 12-nt single-stranded telomeric DNA at 2.1 Å reveals that a UP1 dimer binds two antiparallel DNA strands, with each strand contacting RRM1 of one monomer and RRM2 of the other, providing the structural basis for sequence-specific recognition of telomeric single-stranded overhangs. X-ray crystallography at 2.1 Å resolution Genes & development High 10323862
1996 hnRNP A1 selectively interacts with itself and other hnRNP core proteins (and some SR proteins) via its Gly-rich C-terminal domain; a hydrophobic repeat motif within this domain mediates protein-protein interactions both in vitro (GST pulldown) and in vivo (yeast two-hybrid). In vitro binding assay (pulldown), yeast two-hybrid Journal of molecular biology High 8676373
1998 Both RRM1 and RRM2 of hnRNP A1 are required for alternative splicing function, but each plays a distinct role and their relative position is critical; RRM2 (but not RRM1) can support splicing function when duplicated, demonstrating functional non-equivalence of the quasi-symmetric RRMs. In vitro splicing assay using RRM duplication, deletion, and swap mutants RNA High 9740129
2000 Stress stimuli (osmotic shock, UVC irradiation) activate the MKK3/6-p38 signaling cascade, which phosphorylates hnRNP A1 and causes its cytoplasmic accumulation; this relocalization concomitantly alters the alternative splicing pattern of a reporter pre-mRNA. p38 activation is necessary and sufficient for cytoplasmic accumulation of hnRNP A1. Pharmacological activation/inhibition of p38 pathway; immunofluorescence localization; in vivo splicing reporter assay The Journal of cell biology High 10769024
2001 hnRNP A1 mediates splicing silencing by first binding a high-affinity site in ESS3 of HIV-1 tat exon 3, then cooperatively spreading in the 3'-to-5' direction along the exon. This cooperative propagation is blocked by SF2/ASF (but not SC35) binding to upstream ESE motifs, establishing differential antagonism between negative and positive splicing regulators. In vitro binding assay; splicing reconstitution; gel shift; site-directed mutagenesis Molecular cell High 11779509
2001 hnRNP A1 inhibits HIV-1 tat intron splicing via a novel intronic splicing silencer (ISS), acting at a step subsequent to U2AF binding but mainly at the time of U2 snRNP association. The hnRNP A1 binding site on ISS overlaps with an alternative branch point, physically blocking U2 snRNP entry. hnRNP A1 depletion/add-back to nuclear extracts; UV cross-linking; splicing assay reconstitution The EMBO journal High 11598017
2002 hnRNP A1 binds three sites (ISS, a UAG motif in ESE, and ESS3) in HIV-1 rev/tat pre-mRNA within experimentally supported stem-loop structures. Cooperative network formation between hnRNP A1 molecules at these sites precludes recognition of the branch point and blocks U2 snRNP association. ESS3 stimulates hnRNP A1 binding to ISS and vice versa. RNA secondary structure probing (chemical/enzymatic); UV cross-linking; site-directed mutagenesis; gel retardation RNA High 12458794
2002 hnRNP A1 nucleocytoplasmic shuttling activity is required for normal myelopoiesis; expression of a shuttling-defective mutant enhances apoptosis, suppresses granulocytic differentiation, and downmodulates C/EBPα and Bcl-XL mRNAs. BCR/ABL stabilizes hnRNP A1 by preventing ubiquitin/proteasome-dependent degradation. Dominant-negative mutant expression; colony formation; differentiation assays; in vivo tumor model Molecular and cellular biology High 11884611
2006 hnRNP A1 binds both single-stranded and G-quadruplex telomeric DNA repeats, disrupts G-quadruplex higher-order structure, stimulates telomerase activity in cell extracts (depletion abolished activity; add-back of recombinant hnRNP A1 fully restored it), and associates with human telomeres in vivo by ChIP. In vitro telomerase assay with depletion/reconstitution; G-quadruplex unwinding assay; chromatin immunoprecipitation (ChIP) RNA High 16603717
2008 hnRNP A1 is a reversibly associated component of the 7SK snRNP complex (which contains P-TEFb, HEXIM1, LARP7, and 7SK RNA), in contrast to LARP7 which is a stable core component. Glycerol gradient sedimentation and immunodepletion experiments defined these associations. Glycerol gradient sedimentation; immunodepletion; co-immunoprecipitation Nucleic acids research Medium 18281698
2009 hnRNP A1 can spread cooperatively on RNA in both 3'-to-5' (preferential) and 5'-to-3' directions from a high-affinity initial binding site, unwind RNA hairpins, and displace proteins bound to the RNA. Two distant high-affinity sites facilitate cooperative spreading between them. In vitro binding assay; EMSA; splicing assay with purified proteins; RNA unwinding assay Molecular and cellular biology High 19667073
2009 3020insC NOD2 mutant protein suppresses IL10 transcription by blocking p38-mediated phosphorylation of hnRNP A1, impairing hnRNP A1 binding to the IL10 locus. This was confirmed in patient PBMCs. Phosphorylation assay; ChIP; patient cell analysis Nature immunology Medium 19349988
2010 hnRNP A1 binds the conserved terminal loop of pri-let-7a-1 and inhibits its processing by Drosha, acting as a negative regulator of let-7a biogenesis. hnRNP A1 binding to the terminal loop of pri-let-7a-1 competes with and displaces KSRP, which is a positive regulator of let-7a biogenesis. RNA pulldown; EMSA; in vitro Drosha processing assay; siRNA knockdown; overexpression Nature structural & molecular biology High 20639884
2011 hnRNPA1 displaces RPA from telomeric single-stranded DNA using purified protein, recapitulating a novel activity identified in cell extracts. TERRA inhibits this displacing activity in early S phase; in late S phase when TERRA levels decline, hnRNPA1 displaces RPA. TERRA also promotes POT1 binding by removing hnRNPA1, facilitating the RPA-to-POT1 switch. In vitro competition assay with purified proteins; TERRA EMSA; cell extract fractionation Nature High 21399625
2012 NMR solution structure of hnRNP A1 UP1 shows that the two RRMs interact in solution with a relative orientation similar to the nucleic-acid-bound crystal structure (not the free crystal form), suggesting the two RRMs maintain a single defined orientation that is competent for RNA binding. NMR spectroscopy with segmental isotope labeling Journal of biomolecular NMR High 23247503
2013 Disease-causing mutations in the prion-like domain (PrLD) of hnRNPA1 (e.g., D262N, N267S) strengthen a 'steric zipper' motif, accelerating formation of self-seeding fibrils that cross-seed wild-type hnRNP polymerization. Mutant hnRNPA1 shows excess incorporation into stress granules and drives cytoplasmic inclusion formation in animal models. In vitro fibril formation assay; thioflavin T fluorescence; EM; Drosophila and cell models; stress granule immunofluorescence Nature High 23455423
2013 TERRA can relieve TERRA-mediated inhibition of telomerase when hnRNPA1 is present and binds TERRA; however, when hnRNPA1 is in excess over TERRA, it binds telomeric DNA substrate and itself inhibits telomere extension without directly affecting telomerase catalysis. TERRA and hnRNPA1 thus form a bimolecular switch regulating telomerase access. In vitro telomerase assay; EMSA; competition binding assays with purified proteins Nucleic acids research High 23935072
2013 HNRNPA1 regulates alternative splicing of HMGCR exon 13; overexpression increases exon 13 skipping in an allele-dependent manner (modulated by SNP rs3846662) and specifically stabilizes the HMGCR13(-) transcript, leading to reduced HMGCR enzyme activity and increased LDL-C uptake. Overexpression; RT-PCR splicing assay; HMGCR enzyme activity assay; LDL-C uptake assay; HNRNPA1 binding assay Human molecular genetics Medium 24001602
2014 S6K2 binds and phosphorylates hnRNPA1 on Ser4/6, increasing its association with BCL-XL and XIAP mRNAs to promote their nuclear export. In the cytoplasm, phospho-S4/6-hnRNPA1 dissociates from these mRNAs, de-repressing their IRES-mediated translation. This correlates with phosphorylation-dependent association of hnRNPA1 with 14-3-3, leading to hnRNPA1 sumoylation on K183 and nuclear re-import. In vitro kinase assay; co-immunoprecipitation; RNA-IP; sumoylation assay; S4/6A non-phosphorylatable mutant; nuclear/cytoplasmic fractionation Nucleic acids research High 25324306
2016 TRAF6, a ubiquitin E3 ligase, ubiquitinates hnRNPA1, and this ubiquitination regulates alternative splicing of Arhgap1 pre-mRNA, resulting in activation of Cdc42 and hematopoietic defects. Identified through global ubiquitin proteomics screen. Global ubiquitin proteomics screen; ubiquitination assay; alternative splicing assay; Cdc42 activity assay Nature immunology High 28024152
2017 PRMT5 methylates hnRNP A1 on R218 and R225 (symmetric dimethylation), and this methylation facilitates hnRNP A1 interaction with IRES RNA to promote IRES-dependent translation of Cyclin D1 and c-Myc. In vitro methylation assay; mass spectrometry; IRES reporter assay; RNA pulldown Nucleic acids research High 28115626
2017 Solution NMR structure of hnRNP A1 tandem RRMs bound to short RNA shows that RRM2 binds the upstream motif and RRM1 binds the downstream motif of the bipartite ISS-N1 splicing silencer (which controls SMN exon 7 splicing). Disruption of inter-RRM interaction or loss of RNA binding by either RRM impairs splicing repression. NMR structure determination; in-cell splicing assay; mutagenesis eLife High 28650318
2018 hnRNP A1 forms a 1:1 complex with pri-mir-18a where both RRMs bind cognate sequence motifs in the terminal loop. Terminal loop binding by hnRNP A1 induces an allosteric destabilization of base-pairing in the pri-mir-18a stem, promoting downstream Microprocessor-mediated processing. Integrative structural biology (NMR, SAXS, MD simulations); in vitro processing assay; mutagenesis Nature communications High 29946118
2018 β-hydroxybutyrate (β-HB) directly binds hnRNP A1, and this binding enhances hnRNP A1 association with Oct4 mRNA, stabilizing Oct4 mRNA and increasing Oct4 protein expression, which in turn upregulates Lamin B1 to prevent vascular senescence. Direct binding assay; RNA-IP; mRNA stability assay; in vivo mouse experiments Molecular cell Medium 30197300
2018 The RGG-box of hnRNPA1 specifically interacts with telomere G-quadruplex DNA (but not single-stranded DNA) in a loop-nucleotide-dependent manner, and enhances the G-quadruplex unfolding activity of the adjacent UP1 domain. UP1 and RGG-box act synergistically for complete G-quadruplex unfolding. EMSA; fluorescence binding assay; G-quadruplex unfolding assay; domain deletion analysis Nucleic acids research Medium 30247678
2018 PRMT3 methylates hnRNP A1 at R31 within its RRM domain, and this methylation increases hnRNPA1 RNA-binding activity, promoting binding to ABCG2 mRNA and enhancing its stability, thereby increasing chemoresistance in pancreatic cancer. In vitro methylation assay; mass spectrometry; RNA-IP; R31K mutation analysis; ABCG2 mRNA stability assay Cancers Medium 30577570
2019 Sirtuin deacetylases SIRT1 and SIRT6 deacetylate hnRNP A1 at four specific lysine residues upon glucose starvation; deacetylated hnRNP A1 promotes PKM1 over PKM2 alternative splicing, reducing glycolytic activity in hepatocellular carcinoma cells. Co-immunoprecipitation; in vitro deacetylation assay; mass spectrometry (acetylation site mapping); RT-PCR splicing assay; metabolic assays Oncogene High 30858544
2020 CryoEM structure of hnRNPA1 LC domain amyloid fibrils reveals that the PY-NLS (nuclear localization sequence/M9 domain) forms the major component of the fibril core. Residues critical for Kapβ2 (transportin) binding also stabilize the fibril structure. ALS/MSP mutations cluster within the fibril core. Cryo-electron microscopy structure determination; mutagenesis Nature communications High 33311513
2016 O-GlcNAcylation of hnRNP A1 increases its interaction with transportin1 (Trn1) and promotes nuclear retention, while phosphorylation at the C-terminal domain reduces Trn1 interaction and promotes cytoplasmic accumulation. Novel O-GlcNAcylation and phosphorylation sites were mapped by mass spectrometry. Mass spectrometry (PTM site mapping); co-immunoprecipitation; nuclear/cytoplasmic fractionation; pharmacological modulation of O-GlcNAc levels Experimental cell research Medium 27913144
2021 PRMT4/5/7-mediated arginine methylation regulates hnRNPA1 binding to RNA and controls several alternative splicing events. PRMT7 predominantly methylates a GR motif; multiple methylation sites are proximal to phosphorylation sites. Pharmacological co-inhibition of PRMT4/5/7 shows synergistic effects on cancer cell growth. Mass spectrometry-based methylome profiling; RNA-binding assay; splicing assay; pharmacological inhibition Nature communications High 33782401
2021 The folded RRM domains of hnRNPA1 modify phase separation behavior of its LCD through electrostatic interactions: folded domains compact hnRNPA1 (promoting phase separation) and also increase solubility at higher ionic strengths. The LCD interacts transiently with RRMs in a salt-sensitive manner. SAXS; coarse-grained MD simulations; phase separation assay; turbidity measurements at varying ionic strengths Nucleic acids research High 33577679
2023 Fibril formation from hnRNPA1 LC domain condensates occurs preferentially at the interface of condensates rather than homogeneously inside droplets. Coating the condensate interface with surfactant molecules inhibits fibril formation, suggesting the condensate interface as a mechanistic site for the liquid-to-solid transition. Time-resolved fluorescence microscopy; ThT amyloid assay; surfactant interface coating; confocal and TIRF microscopy Nature chemistry High 37749234
2015 hnRNP A1/A2 depletion by siRNA or cytoplasmic retention by osmotic stress increases association of CDK9 with the 7SK RNA repressor complex, reduces promoter-distal transcription (pausing), and affects transcription of P-TEFb-dependent genes. This establishes a role for hnRNP A1/A2 in transcription elongation via the P-TEFb/7SK pathway. siRNA knockdown; RNA pol II ChIP; CDK9-7SK RNA-IP; RNA-seq; DRB pharmacological inhibition PloS one Medium 26011126
2018 hnRNPA1 and DDX5 share closely linked binding sites on nuclear pre-mRNAs and co-regulate thousands of alternative splicing events. In vivo SHAPE probing reveals RNA structures near their binding sites, suggesting an organized pre-mRNP architecture where hnRNPA1/DDX5 binding sites flank regions of higher chemical reactivity. eCLIP; RNA-seq after RNAi; in vivo SHAPE chemical probing Genes & development Medium 30042133
2019 hnRNPA1 interacts with a G-quadruplex structure in the TRA2B promoter and stimulates TRA2B transcription. Circular dichroism, EMSA, and ChIP confirmed G-quadruplex formation at the promoter and hnRNPA1 binding to it. ChIP; EMSA; circular dichroism; promoter reporter assay; G-quadruplex stabilization Scientific reports Medium 31311954
2019 EV71 3C protease cleaves hnRNP A1, abolishing its binding to the apaf-1 IRES, thereby de-repressing IRES-dependent translation of apaf-1, activating caspase-3, and inducing apoptosis for viral particle release. Protease cleavage assay; RNA pulldown/IRES binding assay; IRES reporter assay; caspase-3 activity measurement PloS one Medium 31498791
2018 lncSHGL recruits hnRNPA1 to enhance translation efficiency of CALM mRNAs (encoding calmodulin), increasing CaM protein levels and activating the PI3K/Akt pathway independently of insulin, thereby suppressing hepatic gluconeogenesis and lipogenesis. RNA pulldown; RIP; polysome profiling; hnRNPA1 overexpression; in vivo mouse experiments Diabetes Medium 29382663
2016 hnRNP A1 directly interacts with the 3' UTR of SIRT1 mRNA, promotes SIRT1 mRNA stability, and increases SIRT1 expression; this delays replicative senescence and prevents oncogene-induced senescence by SIRT1-mediated deacetylation of NF-κB. RNA pulldown; RIP; mRNA stability assay (actinomycin D chase); luciferase 3' UTR reporter; overexpression and knockdown Aging cell Medium 27613566

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 1215 23455423
1995 A nuclear localization domain in the hnRNP A1 protein. The Journal of cell biology 457 7730395
2001 Exon identity established through differential antagonism between exonic splicing silencer-bound hnRNP A1 and enhancer-bound SR proteins. Molecular cell 303 11779509
1999 Crystal structure of the two-RRM domain of hnRNP A1 (UP1) complexed with single-stranded telomeric DNA. Genes & development 303 10323862
2000 The MKK(3/6)-p38-signaling cascade alters the subcellular distribution of hnRNP A1 and modulates alternative splicing regulation. The Journal of cell biology 292 10769024
2011 TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature 280 21399625
2010 Antagonistic role of hnRNP A1 and KSRP in the regulation of let-7a biogenesis. Nature structural & molecular biology 225 20639884
2008 LARP7 is a stable component of the 7SK snRNP while P-TEFb, HEXIM1 and hnRNP A1 are reversibly associated. Nucleic acids research 207 18281698
1996 hnRNP A1 selectively interacts through its Gly-rich domain with different RNA-binding proteins. Journal of molecular biology 169 8676373
2009 A Crohn's disease-associated NOD2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1. Nature immunology 155 19349988
1995 Nucleo-cytoplasmic distribution of human hnRNP proteins: a search for the targeting domains in hnRNP A1. Journal of cell science 151 7769000
2021 Profiling PRMT methylome reveals roles of hnRNPA1 arginine methylation in RNA splicing and cell growth. Nature communications 148 33782401
2001 The hnRNP A1 protein regulates HIV-1 tat splicing via a novel intron silencer element. The EMBO journal 140 11598017
2018 β-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4. Molecular cell 133 30197300
2006 hnRNP A1 associates with telomere ends and stimulates telomerase activity. RNA (New York, N.Y.) 127 16603717
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