Affinage

DIS3

Exosome complex exonuclease RRP44 · UniProt Q9Y2L1

Length
958 aa
Mass
109.0 kDa
Annotated
2026-04-28
68 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DIS3 (Rrp44) is the principal catalytic subunit of the RNA exosome, providing both processive 3′→5′ hydrolytic exoribonuclease activity through its RNB domain and manganese-dependent endonuclease activity through its N-terminal PIN domain, which also serves as the structural anchor to the exosome ring (PMID:17173052, PMID:19129231). RNA substrates reach the DIS3 active site by threading through the exosome's central channel, whose contacts allosterically modulate DIS3 activity; in the nucleus DIS3 degrades PROMPTs, enhancer RNAs, snoRNA precursors, and premature termination products, thereby shaping the RNA polymerase II transcriptome, while in the cytoplasm DIS3 acts as an exosome-independent endonuclease that degrades circular RNAs bearing U-rich motifs (PMID:23404585, PMID:27818140, PMID:26294688, PMID:30840897, PMID:39965568). By clearing aberrant DNA-associated RNAs, DIS3 prevents R-loop accumulation and DNA double-strand breaks, maintains CTCF/cohesin-dependent genome topology, and supports homologous recombination repair (PMID:36215697, PMID:33526923). DIS3 is essential for mitotic progression, B-cell class-switch recombination, spermatogenesis, and pre-implantation embryonic development, where it degrades Pou6f1 mRNA to permit the morula-to-blastocyst transition (PMID:27029730, PMID:36724075, PMID:38953252).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1991 High

    Before DIS3's nuclease identity was known, genetic analysis established it as an essential nuclear protein required for mitosis that genetically interacts with protein phosphatase dis2, framing it as a cell-cycle regulator.

    Evidence Gene disruption, immunoprecipitation, and gel filtration in fission yeast

    PMID:1944266

    Open questions at the time
    • Molecular activity of DIS3 was unknown
    • Mechanism linking DIS3 to mitotic progression unresolved
    • Nature of the 250–350 kDa oligomer uncharacterized
  2. 1998 High

    DIS3 was found to bind Ran GTPase and stimulate RCC1-mediated nucleotide exchange, initially suggesting a role in Ran-dependent nuclear transport; human DIS3 complemented yeast dis3, demonstrating evolutionary conservation.

    Evidence Direct Ran-binding assays, nucleotide release kinetics, and yeast complementation with human DIS3

    PMID:8896453 PMID:9562621

    Open questions at the time
    • RNase activity had not yet been discovered
    • Physiological relevance of the DIS3–Ran interaction for RNA metabolism unclear
    • Whether Ran binding regulates DIS3 nuclease activity unknown
  3. 2006 High

    The paradigm-shifting discovery that DIS3/Rrp44 is solely responsible for all hydrolytic, processive 3′→5′ exoribonuclease activity of the yeast exosome core redefined the exosome as a catalytically inert ring dependent on DIS3 for RNA degradation.

    Evidence Biochemical reconstitution of purified exosome core with catalytically inactive DIS3 mutant; in vivo RNA degradation phenotyping

    PMID:17173052

    Open questions at the time
    • Structural basis for RNA engagement unknown
    • Whether DIS3 possessed additional nuclease activities unresolved
  4. 2007 High

    Structural and functional studies revealed that DIS3 recognizes specific RNA substrates independently of catalysis, binds the RNase PH-ring side of the exosome, and that its RNase activity is required for heterochromatic silencing and kinetochore integrity in mitosis.

    Evidence EM reconstruction of exosome–Rrp44 complex; in vitro binding/degradation of hypomodified tRNA; centromeric silencing assays with RNB domain mutants in fission yeast

    PMID:17380189 PMID:17643380 PMID:17942686

    Open questions at the time
    • High-resolution atomic structure of DIS3 with RNA not yet available
    • PIN domain nuclease activity not yet identified
    • Mechanism linking RNA degradation to kinetochore function unclear
  5. 2008 High

    The 2.3 Å crystal structure of Rrp44 with ssRNA revealed that, unlike bacterial RNase II, OB-fold domains occlude the canonical RNA path, forcing RNA through an alternative route — explaining how DIS3 can unwind duplexes.

    Evidence X-ray crystallography of Rrp44–ssRNA complex at 2.3 Å

    PMID:18374646

    Open questions at the time
    • Structure of DIS3 in context of the full exosome not yet determined
    • Endonuclease mechanism unresolved
  6. 2009 High

    The PIN domain was identified as a distinct Mn²⁺-dependent endonuclease that also serves as the sole structural tether of DIS3 to the exosome core, establishing DIS3 as a dual-nuclease enzyme.

    Evidence In vitro endonuclease assay with PIN active-site mutants; deletion mapping of exosome core association

    PMID:19129231

    Open questions at the time
    • Whether PIN endonuclease activity requires RNA threading through the exosome channel unknown
    • Relative contributions of endo- vs exo-nuclease activity in vivo unresolved
  7. 2013 High

    Channel-threading was demonstrated to be required for both endo- and exonuclease activities: an Rrp41 channel-blocking mutation inhibited both DIS3 catalytic modes, establishing the exosome ring as an allosteric regulator of DIS3.

    Evidence In vivo and in vitro analysis of Rrp41 channel mutant in yeast and reconstituted Chaetomium thermophilum exosomes

    PMID:23404585

    Open questions at the time
    • Structural basis for allosteric inhibition at atomic resolution pending
    • Whether channel threading applies equally to all substrate classes unknown
  8. 2015 High

    In human cells, PAR-CLIP and catalytic-mutant transcriptomics defined DIS3's direct nuclear substrates — PROMPTs, premature termination products, and snoRNA precursors — establishing it as the primary nucleoplasmic surveillance nuclease.

    Evidence PAR-CLIP of DIS3 in HEK293 cells; transcriptomics with double-catalytic-site mutant

    PMID:26294688

    Open questions at the time
    • Relative kinetics of DIS3 vs RRP6 on shared substrates not resolved
    • Whether DIS3 acts on these substrates in complex with MTR4/NEXT was not dissected
  9. 2016 High

    Crystal structure of the 11-subunit nuclear exosome with RNA revealed the complete RNA path to both DIS3 and Rrp6, showed that core contacts allosterically inhibit DIS3, and demonstrated DIS3 uniquely degrades 3′-phosphate substrates — and CDK1 phosphorylation was shown to inhibit DIS3 exonuclease activity, linking its regulation to the cell cycle.

    Evidence 3.1 Å crystal structure of nuclear exosome–RNA; CDK1 phosphorylation-site mutagenesis in Drosophila and genetic analysis across fly, worm, and mouse

    PMID:27029730 PMID:27818140

    Open questions at the time
    • Dynamics of allosteric switching between Rrp6 and DIS3 pathways unknown
    • Identity of CDK1 phosphorylation-responsive substrates in vivo unresolved
  10. 2019 High

    Rapid auxin-mediated DIS3 depletion confirmed DIS3 — not EXOSC10 — as the primary degrader of enhancer RNAs and PROMPTs within minutes, and a parallel study revealed DIS3 integrates with proteostasis by degrading chaperone mRNAs, with stress-dependent ubiquitination of DIS3 controlled by Hsp70/Sis1.

    Evidence Auxin-inducible degron with 60-min RNA-seq in human cells; co-IP of DIS3–Sis1/Ssa1 and ubiquitination assays in yeast

    PMID:30840897 PMID:31428776

    Open questions at the time
    • Ubiquitin ligase targeting DIS3 not identified
    • Whether chaperone-mediated DIS3 regulation is conserved in mammals unknown
  11. 2021 High

    DIS3 was shown to maintain 3D genome architecture in B cells by degrading RNAs at CTCF-binding elements; its loss disrupted CTCF/cohesin positioning at the Igh locus, impaired class-switch recombination, and increased chromosomal translocations.

    Evidence Conditional Dis3 KO in mouse B cells; Hi-C, ChIP-seq for CTCF/cohesin, and immunoglobulin sequencing

    PMID:33526923

    Open questions at the time
    • Whether DIS3-dependent RNA clearance at CTCF sites is a general genome-wide mechanism or Igh-specific
    • Direct RNA substrates at CTCF sites not individually identified
  12. 2022 High

    DIS3 inactivation was found to cause R-loop accumulation, DNA double-strand breaks, and impaired homologous recombination repair, providing a mechanistic link between exosome dysfunction and genome instability and revealing synthetic lethality with PARP inhibition.

    Evidence DIS3 inactivation in myeloma cell lines; R-loop staining (S9.6), γH2AX foci, HR repair assays, and PARP inhibitor sensitivity

    PMID:36215697

    Open questions at the time
    • Whether R-loop accumulation is a direct or indirect consequence of specific RNA substrate accumulation
    • Therapeutic potential of PARP inhibitor synergy not validated in vivo
  13. 2023 High

    DIS3 was shown to be essential for pre-implantation embryogenesis: Dis3-null embryos arrest at the morula stage due to accumulation of Pou6f1 mRNA, which represses Nanog and Cdx2 transcription; microinjection of Dis3 mRNA rescues the phenotype.

    Evidence Dis3 knockout mouse embryos; single-embryo RNA-seq; mRNA microinjection rescue

    PMID:36724075

    Open questions at the time
    • How DIS3 selectively targets Pou6f1 mRNA is unknown
    • Whether other transcription factors are similarly regulated during implantation
  14. 2025 High

    A new exosome-independent function was established: cytoplasmic DIS3 uses its PIN endonuclease domain alone to degrade circular RNAs bearing U-rich motifs, expanding DIS3's role beyond the exosome complex.

    Evidence In vitro circRNA cleavage reconstituted without exosome core; DIS3 depletion RNA-seq showing >60% circRNA upregulation; U-rich motif enrichment

    PMID:39965568 PMID:40440169

    Open questions at the time
    • How DIS3 recognizes U-rich motifs structurally is unresolved
    • Whether cytoplasmic DIS3 has additional exosome-independent substrates beyond circRNAs
    • Regulation of cytoplasmic vs nuclear DIS3 pools not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for DIS3's exosome-independent circRNA recognition, the identity of the ubiquitin ligase controlling DIS3 turnover, whether the DIS3–Ran interaction modulates RNA degradation, and how CDK1 phosphorylation coordinates DIS3 substrate selection through the cell cycle.
  • Structural basis for U-rich circRNA recognition by the PIN domain
  • Identity of the E3 ligase that ubiquitinates DIS3
  • Functional significance of DIS3–Ran binding for RNA metabolism
  • Mechanism by which CDK1 phosphorylation selects DIS3 substrates in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 7 GO:0016787 hydrolase activity 4 GO:0003723 RNA binding 3
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3 GO:0005730 nucleolus 1
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-1640170 Cell Cycle 3 R-HSA-1266738 Developmental Biology 2 R-HSA-4839726 Chromatin organization 2 R-HSA-73894 DNA Repair 1
Partners
EXOSC10EXOSC3EXOSC4EXOSC5MPP6MTREXRANRCC1
Complex memberships
RNA exosome

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Dis3 (Rrp44) is solely responsible for the hydrolytic, processive, Mg2+-dependent 3'→5' exoribonuclease activity of the yeast exosome core. A catalytically inactive Dis3 mutant abolishes all exosome core activity in vitro, while mutation of Rrp41's phosphorolytic site has no phenotypic consequence. The exosome ring subunits mediate interactions with protein partners but do not contribute catalytic activity. Biochemical reconstitution of purified exosome core; in vitro exonuclease assays; catalytically-inactive Dis3 point mutant; comparison with Rrp41 phosphorolytic mutant; in vivo RNA degradation phenotyping Nature structural & molecular biology High 17173052
2008 Crystal structure of S. cerevisiae Rrp44 (Dis3) at 2.3 Å in complex with single-stranded RNA reveals that, unlike bacterial RNase II, the OB-fold domains occlude the RNA-binding path of RNase II and RNA is threaded to the catalytic site via an alternative route, suggesting a mechanism for RNA-duplex unwinding. X-ray crystallography (2.3 Å) of Rrp44–ssRNA complex; structural comparison with bacterial RNase II Molecular cell High 18374646
2007 Rrp44/Dis3 directly recognizes specific RNA substrates (hypomodified tRNA lacking m1A58) independently of its catalytic activity; recognition maps to a distinct region of the protein from the catalytic domain, and complete degradation requires both Rrp44's catalytic activity and TRAMP poly(A) polymerase activity. Recombinant Rrp44 in vitro binding and degradation assays; TRAMP pulldown/reconstitution; in vivo genetic separation of recognition and catalytic mutations Molecular cell High 17643380
2009 The N-terminal PIN domain of Rrp44/Dis3 harbors manganese-dependent endonuclease activity (abolished by four point mutations in PIN metal-binding residues) and is both necessary and sufficient for association with the exosome core, thus serving dual functions as a nuclease and structural tethering element. In vitro endonuclease assay with recombinant Rrp44; PIN domain point mutants; deletion mapping of exosome core association; in vivo growth complementation assays Nucleic acids research High 19129231
2007 EM reconstruction reveals that Rrp44 binds the RNase PH-domain side of the exosome core; its C-terminal RNase II-type active site is anchored mainly to Rrp45 and Rrp43, while the N-terminal domain is anchored to Rrp41 and may function as a gating element restricting RNA access to the active site. Electron microscopy reconstruction of core and Rrp44-bound exosome complexes Proceedings of the National Academy of Sciences of the United States of America High 17942686
2016 Crystal structure at 3.1 Å of the 11-subunit nuclear exosome bound to RNA reveals: (1) an extended RNA path to Rrp6 penetrating the non-catalytic core; (2) contacts between the non-catalytic core and Rrp44 that allosterically inhibit its exoribonuclease activity; and (3) Rrp44 can degrade 3'-phosphate RNA substrates whereas Rrp6 cannot. X-ray crystallography (3.1 Å) of 11-subunit nuclear exosome-RNA complex; in vitro exonuclease assays with reconstituted exosome complexes using 3'-phosphate and 3'-OH RNA substrates Molecular cell High 27818140
2013 RNA substrates reach the Dis3 exonucleolytic active site through passage through the central channel of the exosome ring; the central channel also controls Dis3 endonucleolytic activity. An Rrp41 mutant with a partially blocked channel inhibits both endo- and exonucleolytic Dis3 activities in vivo and in vitro. In vivo growth phenotyping and RNA analysis in Rrp41 channel mutant yeast; in vitro reconstitution of Chaetomium thermophilum exosomes from recombinant subunits; synthetic lethality with Rrp6 deletion Nucleic acids research High 23404585
1996 Dis3 binds directly to Ran GTPase (in a 1:1 molar ratio) and enhances the nucleotide exchange (GEF) activity of RCC1 on Ran by reducing its Km by half without changing kcat. In vivo, Dis3 forms a heterotrimeric oligomer with Ran (Spi1) and RCC1 (Pim1) homologs. Yeast two-hybrid; direct binding assay; nucleotide release kinetics assay; gel filtration of native complexes The EMBO journal High 8896453
1991 Fission yeast Dis3 protein is a 110-kDa nuclear protein that exists as a 250-350 kDa oligomer, is essential for cell viability and mitosis, and genetically interacts with the type 1 protein phosphatase gene dis2 (double mutant is lethal); increased dis3 dosage suppresses the cdc25 wee1 phenotype. Gene cloning, disruption, and complementation; anti-Dis3 immunoprecipitation and gel filtration; genetic double-mutant analysis; dosage suppression assay Molecular and cellular biology High 1944266
2007 Dis3 RNase activity (RNase II domain mutation) is required for proper kinetochore formation and microtubule-kinetochore interactions in fission yeast mitosis. Dis3 loss causes mitotic checkpoint (Mad2-dependent) arrest and loss of heterochromatic silencing at centromeric outer repeats and central core regions. In vitro RNase activity assay of dis3-54 mutant protein; genetic double-mutant analysis (Mad2 dependency); ura4+ reporter silencing assay; micrococcal nuclease chromatin assay PloS one High 17380189
2015 Human DIS3, using both its exonucleolytic (RNB) and endonucleolytic (PIN) active sites, degrades PROMPTs, premature RNA Pol II termination products, and snoRNA precursors in the nucleoplasm; DIS3 is the main snoRNA-processing enzyme, while EXOSC10/RRP6 controls mature snoRNA levels. PAR-CLIP of DIS3 in HEK293 cells; transcriptomics of cells expressing double-catalytic-site mutant DIS3; analysis of NEAT1/paraspeckle phenotype Genome research High 26294688
2019 Rapid auxin-induced depletion of DIS3 in human cells causes substantial accumulation of enhancer RNAs, PROMPTs, and products of premature cleavage and polyadenylation within 60 minutes, phenotypes not observed upon rapid EXOSC10 depletion, establishing DIS3 as the primary exoribonuclease for these transcripts. Auxin-inducible degron rapid protein depletion; RNA-seq at 60 min post-depletion; comparison with EXOSC10 depletion and XRN2 depletion Cell reports High 30840897
2010 Human Dis3 (hDis3) localizes to the nucleus, while the paralog hDis3L1 localizes exclusively to the cytoplasm and associates with the exosome core. hDis3L1 degrades RNA exoribonucleolytically via its RNB domain and is involved in cytoplasmic RNA decay (knockdown elevates poly(A)-tailed 28S rRNA degradation intermediates). Immunoaffinity purification and mass spectrometry of human exosome; co-immunoprecipitation; immunofluorescence localization; in vitro RNase assay; siRNA knockdown with Northern blot The EMBO journal High 20531389
2009 Drosophila Dis3 nuclear localization requires a C-terminal classical NLS and interaction with importin-α3. The N-terminal domain of Dis3 is necessary and sufficient for interactions with core exosome proteins, while binding to Rrp6 and importin-α3 is independent of core interactions and occurs through different regions. Dis3 and Rrp6 exhibit coordinated nuclear enrichment/exclusion. N-terminal domain deletion mutants; co-immunoprecipitation; fluorescence microscopy; NLS mutation experiments in Drosophila S2 cells Traffic (Copenhagen, Denmark) Medium 19220816
2010 Drosophila Dis3 N-terminus is sufficient for endoribonuclease activity in vitro; proper N-terminal domain structure is critical for full-length polypeptide activity; the N-terminus mediates interactions with core exosome proteins and contributes to nuclear localization. In vitro ribonuclease assay of dDis3 domain deletion mutants; co-immunoprecipitation in S2 cells; fluorescence microscopy Nucleic acids research Medium 20421210
2015 DIS3 promotes maturation of let-7 miRNAs by degrading LIN28B mRNA in the cytoplasm, thereby relieving LIN28B-mediated inhibition of let-7 processing; DIS3 inactivation increases LIN28B protein, decreases mature let-7, and enhances translation of let-7 targets MYC and RAS. DIS3 knockdown/overexpression in myeloma cells; LIN28B mRNA stability assay; miRNA quantification; polysome profiling; luciferase reporter assay Nucleic acids research Medium 25925570
2016 Dis3 exonuclease activity (but not endonuclease activity) is required for mitotic cell division in Drosophila; loss of dis3 causes mitotic delay, aneuploidy, and overcondensed chromosomes. A conserved CDK1 phosphorylation site on Dis3, when phosphorylated, inhibits its exonuclease but not endonuclease activity. Modest reduction of dis3 function enhances cell proliferation in the presence of elevated Ras activity. dis3 null alleles in Drosophila; exonuclease-specific and endonuclease-specific mutants; CDK1 phosphorylation site mutagenesis; genetic interaction with Ras; double-mutant analysis in C. elegans and mouse B cells Genetics High 27029730
2021 DIS3 deficiency in mouse B cells causes accumulation of DNA-associated RNAs flanking CTCF-binding elements, decreased CTCF binding to those elements, and disorganized cohesin localization, disrupting Igh locus topological architecture and resulting in altered AID activity, decreased class-switch recombination, and increased chromosomal translocations. Conditional Dis3 knockout mouse model; single-embryo RNA-seq; Hi-C/3D genome analysis; ChIP-seq for CTCF and cohesin; immunoglobulin sequencing Nature genetics High 33526923
2022 DIS3 inactivation causes accumulation of DNA:RNA hybrids (R-loops) that induce genomic DNA double-strand breaks and prevent binding of homologous recombination machinery to DSBs, impairing HR repair and sensitizing cells to PARP inhibitors. TCGA dataset analysis; DIS3 inactivation in myeloma cell lines; R-loop immunofluorescence (S9.6 antibody); γH2AX foci; HR repair assay; PARP inhibitor sensitivity assay The EMBO journal High 36215697
2023 Mouse embryonic Dis3 knockout arrests development at the morula stage by preventing degradation of Pou6f1 mRNA; accumulation of Pou6f1 protein represses Nanog and Cdx2 transcription, disrupting morula-to-blastocyst transition. Microinjection of Dis3 mRNA rescues this phenotype. Dis3 knockout mouse embryos; single-embryo RNA-seq; microinjection rescue; Dis3 point mutant blastomere injection; Dis3-null ESC derivation Cell reports High 36724075
2025 DIS3 endonucleolytic activity (PIN domain) is responsible for degradation of circular RNAs in the cytoplasm, independently of the RNA exosome complex. DIS3 preferentially degrades circRNAs containing U-rich motifs, and DIS3 depletion upregulates >60% of circRNAs with little effect on their linear cognates. DIS3 depletion RNA-seq; in vitro circRNA degradation assay; exosome-independent in vitro reconstitution; U-rich motif enrichment analysis; synthetic circRNA stability assay with/without U-rich motifs Molecular cell High 39965568
2025 Cytoplasmic DIS3 functions as a stand-alone endoribonuclease (via PIN domain), independently of the exosome core, to degrade circular RNAs. DIS3 partially resides in the cytoplasm, and its knockdown moderately stabilizes selected circRNAs. Biochemical fractionation; in vitro circRNA cleavage assay without exosome core; DIS3 knockdown with circRNA quantification by RNA-seq Cell reports Medium 40440169
2013 Mutation of conserved RNB domain residue Y595 in Rrp44/Dis3 changes the final degradation product from 4 to 5 nucleotides, confirming that this residue mediates stacking of RNA substrate in the catalytic cavity. Mutation of Q892 increases enzyme activity in vitro. Site-directed mutagenesis of Rrp44 RNB domain; in vitro exonuclease assay; in vivo growth and RNA processing analysis; molecular dynamics modeling PloS one Medium 24265673
2018 Two DIS3 protein-coding isoforms arise from alternative splicing differing in their PIN domain size; isoform 2 (with shorter PIN domain) has greater endonuclease activity than isoform 1 despite missing conserved PIN residues. In multiple myeloma cells, isoform 1 predominates over isoform 2. In vitro endonuclease activity assays of full-length isoforms and isolated PIN domains; RT-PCR quantification of isoforms in patient samples and cell lines; structural analysis The Biochemical journal Medium 29802118
2018 Elimination of the 01/A'-A0 pre-rRNA 5'-ETS by-product in human cells proceeds exclusively in the 3'→5' direction in multiple phases: after an unknown nuclease initiates, RRP6 executes the decay with some DIS3 contribution, while the ultimate phase involves predominantly DIS3. Northern blot and RT-PCR analysis of DIS3/RRP6 knockdown cells; XRN2 knockdown comparison; kinetic analysis of 5'-ETS fragment accumulation RNA (New York, N.Y.) Medium 30266864
2020 Yeast Rrp44/Dis3 localizes predominantly to the nucleus and concentrates in the nucleolus (where early pre-rRNA processing takes place); exosome core subunits Rrp41 and Rrp43 similarly accumulate in the nucleolus. Confocal fluorescence microscopy with GFP-tagged proteins in S. cerevisiae; subcellular fractionation The Journal of biological chemistry Medium 32554806
2019 In yeast, Dis3 ribonuclease suppresses proteostasis/protein quality control activity in unstressed cells by degrading mRNAs encoding Hsp70 cofactors (Sis1, Ydj1, Fes1). Dis3 is stabilized by binding to Sis1 and Hsp70s Ssa1/2; upon heat stress, loss of Sis1/Ssa1/2 availability triggers Dis3 ubiquitination and degradation, stabilizing chaperone mRNAs. PolyQ-expanded huntingtin delays Dis3 degradation and hinders chaperone mRNA stabilization. mRNA stability assays; Co-immunoprecipitation (Dis3-Sis1, Dis3-Ssa1/2); ubiquitination assay; DIS3 knockdown/overexpression; huntingtin-expressing cells heat stress response Nucleic acids research Medium 31428776
2024 Male germ-cell-specific Dis3 conditional knockout in mice disrupts the first and subsequent waves of spermatogenesis, leading to Sertoli cell-only phenotype and sterility. Dis3 deficiency abolishes RNA degradation and causes accumulation of PROMPTs in testes; scRNA-seq shows disrupted RNA metabolism and impaired early germline cell development in spermatogonia. Conditional knockout mouse (Dis3 flox × germ-cell-Cre); histology; bulk RNA-seq; scRNA-seq; immunofluorescence Development (Cambridge, England) High 38953252
2022 MPP6 stimulates both RRP6 and DIS3 to degrade a specific subset of MTR4-sensitive nuclear RNA substrates; MTR4 binding to the exosome core via MPP6 is essential for this activity and is not functionally equivalent to MTR4 recruitment by RRP6. siRNA knockdown of MPP6, RRP6, DIS3 in human cells; poly(A)+ RNA accumulation assay; genome-wide RNA-seq substrate classification; functional rescue experiments Nucleic acids research Medium 35902094
1998 Human DIS3 protein binds to both GTP-Ran and GDP-Ran and enhances RCC1-stimulated nucleotide release from Ran in a dose-dependent manner; human DIS3 partially complements S. cerevisiae dis3 temperature-sensitive mutant, demonstrating evolutionary conservation of function. Cloning of human DIS3 cDNA; yeast complementation assay; direct Ran-binding assay; nucleotide release kinetics Journal of biochemistry Medium 9562621

Source papers

Stage 0 corpus · 68 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 A single subunit, Dis3, is essentially responsible for yeast exosome core activity. Nature structural & molecular biology 353 17173052
2009 The N-terminal PIN domain of the exosome subunit Rrp44 harbors endonuclease activity and tethers Rrp44 to the yeast core exosome. Nucleic acids research 183 19129231
2008 Structure of the active subunit of the yeast exosome core, Rrp44: diverse modes of substrate recruitment in the RNase II nuclease family. Molecular cell 159 18374646
2007 The exosome subunit Rrp44 plays a direct role in RNA substrate recognition. Molecular cell 125 17643380
2010 Dis3-like 1: a novel exoribonuclease associated with the human exosome. The EMBO journal 119 20531389
2007 Architecture of the yeast Rrp44 exosome complex suggests routes of RNA recruitment for 3' end processing. Proceedings of the National Academy of Sciences of the United States of America 92 17942686
2002 An evolutionarily conserved fission yeast protein, Ned1, implicated in normal nuclear morphology and chromosome stability, interacts with Dis3, Pim1/RCC1 and an essential nucleoporin. Journal of cell science 88 12376568
2016 Nuclear RNA Exosome at 3.1 Å Reveals Substrate Specificities, RNA Paths, and Allosteric Inhibition of Rrp44/Dis3. Molecular cell 80 27818140
1996 Dis3, implicated in mitotic control, binds directly to Ran and enhances the GEF activity of RCC1. The EMBO journal 78 8896453
1991 The fission yeast dis3+ gene encodes a 110-kDa essential protein implicated in mitotic control. Molecular and cellular biology 77 1944266
2015 DIS3 shapes the RNA polymerase II transcriptome in humans by degrading a variety of unwanted transcripts. Genome research 73 26294688
2007 Ribonuclease activity of Dis3 is required for mitotic progression and provides a possible link between heterochromatin and kinetochore function. PloS one 68 17380189
2019 Rapid Depletion of DIS3, EXOSC10, or XRN2 Reveals the Immediate Impact of Exoribonucleolysis on Nuclear RNA Metabolism and Transcriptional Control. Cell reports 62 30840897
2014 The molecular spectrum and clinical impact of DIS3 mutations in multiple myeloma. British journal of haematology 58 25521164
2021 Noncoding RNA processing by DIS3 regulates chromosomal architecture and somatic hypermutation in B cells. Nature genetics 53 33526923
1998 Human dis3p, which binds to either GTP- or GDP-Ran, complements Saccharomyces cerevisiae dis3. Journal of biochemistry 51 9562621
2013 The RNA exosome complex central channel controls both exonuclease and endonuclease Dis3 activities in vivo and in vitro. Nucleic acids research 50 23404585
2010 Genome-wide analysis reveals distinct substrate specificities of Rrp6, Dis3, and core exosome subunits. RNA (New York, N.Y.) 48 20185544
2015 The 3' to 5' Exoribonuclease DIS3: From Structure and Mechanisms to Biological Functions and Role in Human Disease. Biomolecules 47 26193331
2013 Arabidopsis AtRRP44A is the functional homolog of Rrp44/Dis3, an exosome component, is essential for viability and is required for RNA processing and degradation. PloS one 41 24244451
2015 A compendium of DIS3 mutations and associated transcriptional signatures in plasma cell dyscrasias. Oncotarget 40 26305418
2020 BRAF and DIS3 Mutations Associate with Adverse Outcome in a Long-term Follow-up of Patients with Multiple Myeloma. Clinical cancer research : an official journal of the American Association for Cancer Research 39 31988198
2014 Gene-dosage dependent overexpression at the 13q amplicon identifies DIS3 as candidate oncogene in colorectal cancer progression. Genes, chromosomes & cancer 32 24478024
2012 The ribonuclease Dis3 is an essential regulator of the developmental transcriptome. BMC genomics 32 22853036
1997 Isolation of murine and human homologues of the fission-yeast dis3+ gene encoding a mitotic-control protein and its overexpression in cancer cells with progressive phenotype. Cancer research 30 9041195
2015 The ribonuclease DIS3 promotes let-7 miRNA maturation by degrading the pluripotency factor LIN28B mRNA. Nucleic acids research 29 25925570
2016 Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression. Human molecular genetics 25 28172817
2005 Drosophila gene tazman, an orthologue of the yeast exosome component Rrp44p/Dis3, is differentially expressed during development. Developmental dynamics : an official publication of the American Association of Anatomists 25 15704111
2015 The 3'-5' exoribonuclease Dis3 regulates the expression of specific microRNAs in Drosophila wing imaginal discs. RNA biology 23 25892215
2019 The Implication of mRNA Degradation Disorders on Human DISease: Focus on DIS3 and DIS3-Like Enzymes. Advances in experimental medicine and biology 21 31342438
2025 Degradation of circular RNA by the ribonuclease DIS3. Molecular cell 20 39965568
2022 DIS3 mutations in multiple myeloma impact the transcriptional signature and clinical outcome. Haematologica 20 33951891
2022 Loss of ribonuclease DIS3 hampers genome integrity in myeloma by disrupting DNA:RNA hybrid metabolism. The EMBO journal 18 36215697
2011 Pronounced and extensive microtubule defects in a Saccharomyces cerevisiae DIS3 mutant. Yeast (Chichester, England) 18 21919057
2010 Drosophila melanogaster Dis3 N-terminal domains are required for ribonuclease activities, nuclear localization and exosome interactions. Nucleic acids research 18 20421210
2009 Interdependent nucleocytoplasmic trafficking and interactions of Dis3 with Rrp6, the core exosome and importin-alpha3. Traffic (Copenhagen, Denmark) 18 19220816
2016 Collaborative Control of Cell Cycle Progression by the RNA Exonuclease Dis3 and Ras Is Conserved Across Species. Genetics 17 27029730
2018 Elimination of 01/A'-A0 pre-rRNA processing by-product in human cells involves cooperative action of two nuclear exosome-associated nucleases: RRP6 and DIS3. RNA (New York, N.Y.) 15 30266864
2024 DIS3 depletion in multiple myeloma causes extensive perturbation in cell cycle progression and centrosome amplification. Haematologica 14 37439377
2023 DIS3: The Enigmatic Gene in Multiple Myeloma. International journal of molecular sciences 13 36835493
2021 Repeated Evolution of Inactive Pseudonucleases in a Fungal Branch of the Dis3/RNase II Family of Nucleases. Molecular biology and evolution 13 33313834
2023 RNA exosome ribonuclease DIS3 degrades Pou6f1 to promote mouse pre-implantation cell differentiation. Cell reports 12 36724075
2019 Exonuclease domain mutants of yeast DIS3 display genome instability. Nucleus (Austin, Tex.) 12 30724665
2018 DIS3 isoforms vary in their endoribonuclease activity and are differentially expressed within haematological cancers. The Biochemical journal 11 29802118
2009 Characterization of the Drosophila melanogaster Dis3 ribonuclease. Biochemical and biophysical research communications 11 19800864
2020 Nucleolar localization of the yeast RNA exosome subunit Rrp44 hints at early pre-rRNA processing as its main function. The Journal of biological chemistry 10 32554806
2013 Modulating the RNA processing and decay by the exosome: altering Rrp44/Dis3 activity and end-product. PloS one 10 24265673
2019 TRIBE Uncovers the Role of Dis3 in Shaping the Dynamic Transcriptome in Malaria Parasites. Frontiers in cell and developmental biology 9 31737630
2019 Trypanosoma brucei RRP44 is involved in an early stage of large ribosomal subunit RNA maturation. RNA biology 8 30593255
2018 A204E mutation in Nav1.4 DIS3 exerts gain- and loss-of-function effects that lead to periodic paralysis combining hyper- with hypo-kalaemic signs. Scientific reports 8 30420713
2022 MPP6 stimulates both RRP6 and DIS3 to degrade a specified subset of MTR4-sensitive substrates in the human nucleus. Nucleic acids research 7 35902094
2024 DIS3 ribonuclease is essential for spermatogenesis and male fertility in mice. Development (Cambridge, England) 6 38953252
2023 Trypanosoma brucei RRP44: a versatile enzyme for processing structured and non-structured RNA substrates. Nucleic acids research 6 36583334
2025 Cytoplasmic DIS3 is an exosome-independent endoribonuclease with catalytic activity toward circular RNAs. Cell reports 5 40440169
2023 Dissecting Trypanosoma brucei RRP44 function in the maturation of segmented ribosomal RNA using a regulated genetic complementation system. Nucleic acids research 3 36610751
2023 DIS3 Variants are Associated With Primary Ovarian Insufficiency: Importance of Transcription/Translation in Oogenesis. The Journal of clinical endocrinology and metabolism 3 36869713
2012 Dis3- and exosome subunit-responsive 3' mRNA instability elements. Biochemical and biophysical research communications 3 22668878
2025 Functional characterization of human recessive DIS3 variants in premature ovarian insufficiency†. Biology of reproduction 2 39400047
2022 MicroRNA-125a/b-5p promotes malignant behavior in multiple myeloma cells and xenograft tumor growth by targeting DIS3. The Kaohsiung journal of medical sciences 2 35394705
2019 Post-transcriptional negative feedback regulation of proteostasis through the Dis3 ribonuclease and its disruption by polyQ-expanded Huntingtin. Nucleic acids research 2 31428776
2023 Epididymal DIS3 exosome ribonuclease is not necessary for mouse sperm maturation or fertility. Biochemical and biophysical research communications 1 37172450
2026 DIS3 ribonuclease regulates Sertoli cell development to support spermatogenesis in mice. Development (Cambridge, England) 0 41645813
2026 DIS3 mutations enhance AID-driven translocations during B-cell activation, promoting transformation to multiple myeloma. Nature communications 0 41832173
2026 Genome-Wide Association Study Suggests rrp44 Is a Key Regulator of Growth Traits in Channel Catfish (Ictalurus punctatus). Current issues in molecular biology 0 42042080
2025 The Legionella pneumophila Dot/Icm Type IV Secretion System is Structurally and Functionally Resilient in Absence of Species-specific Proteins Dis2 and Dis3. Journal of molecular biology 0 40581092
2025 DIS3 licenses B cells for plasma cell differentiation in humans. Cellular & molecular immunology 0 41286079
2023 Co-existence of KMT2A::SEPTIN6 fusion and DIS3 variant in a pediatric case with acute myeloid leukemia: a case report and literature review. Frontiers in oncology 0 38152368
2019 [Effect of Expression Regulation of Mitotic Control Protein DIS3 on Proliferation of 3 Cell Lines of Human Myeloma]. Zhongguo shi yan xue ye xue za zhi 0 31839059