Affinage

DIS3

Exosome complex exonuclease RRP44 · UniProt Q9Y2L1

Length
958 aa
Mass
109.0 kDa
Annotated
2026-06-09
70 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DIS3 (Rrp44) is the principal catalytic engine of the eukaryotic RNA exosome, a ribonuclease that shapes both the nuclear and cytoplasmic transcriptomes and that links RNA turnover to chromosome segregation, genome architecture, and cell proliferation (PMID:17173052, PMID:26294688). It carries two separable nuclease activities: a processive, Mg2+-dependent 3'→5' hydrolytic exoribonuclease in its C-terminal RNB domain that accounts for essentially all exonucleolytic activity of the exosome core, and an independent Mn2+-dependent endonuclease in its N-terminal PIN domain, which is also necessary and sufficient for association with the exosome ring (PMID:17173052, PMID:19129231). Crystallographic and EM work showed that the OB-fold domains occlude the canonical RNA-binding path, forcing substrates to thread to the active site through an alternative route capable of unwinding duplexes, while contacts between the non-catalytic exosome core and the central channel allosterically restrict DIS3 access and activity (PMID:18374646, PMID:17942686, PMID:27818140, PMID:23404585). In the nucleus, DIS3 degrades PROMPTs, enhancer RNAs, premature Pol II termination and cleavage/polyadenylation products, and snoRNA precursors—a substrate set distinct from that of the co-resident exonuclease EXOSC10/RRP6, with which it acts largely independently (PMID:26294688, PMID:30840897, PMID:30266864, PMID:20185544). Acting on chromatin-associated RNAs, DIS3 controls genome organization: its loss in B cells disrupts CTCF/cohesin distribution and topologically associating domain structure at the Igh locus and promotes AID-driven chromosomal translocations, and the disease-associated G766R variant drives pristane-induced plasmacytomas through aberrant AID activity (PMID:33526923, PMID:41832173). DIS3 additionally functions as a stand-alone, exosome-independent cytoplasmic endonuclease that degrades the majority of circRNAs via U-rich motif recognition and generates tRNA halves that regulate translation and longevity (PMID:39965568, PMID:40440169, PMID:42168172), and it regulates developmental and proteostatic gene expression by degrading specific mRNAs including LIN28B, Pou6f1, and chaperone cofactor transcripts (PMID:25925570, PMID:36724075, PMID:31428776). A clinically relevant DIS3 mutation linking the gene to myeloma and plasma-cell malignancy operates through impaired exoribonucleolytic activity and accumulation on aberrant AID target RNA (PMID:41832173).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1991 Medium

    Before any biochemical activity was known, genetics established Dis3 as an essential nuclear factor for accurate chromosome segregation, framing it as a mitotic-control gene.

    Evidence Gene cloning, disruption, immunolocalization, and dosage suppression in fission yeast

    PMID:1944266

    Open questions at the time
    • No molecular activity assigned at this stage
    • Mechanism connecting Dis3 to chromosome disjunction undefined
  2. 1996 Medium

    An early biochemical link placed Dis3 in nucleotide-exchange regulation by showing direct binding to Ran and stimulation of RCC1 GEF activity, a connection not integrated with its later-defined ribonuclease role.

    Evidence Two-hybrid, direct binding, GEF kinetics, and co-fractionation in yeast

    PMID:8896453

    Open questions at the time
    • Relationship to RNA-degradation function unresolved
    • Physiological relevance of the Ran/RCC1 interaction in higher eukaryotes untested
  3. 2006 High

    The central unknown of which exosome subunit was catalytic was resolved by showing Dis3, not the phosphorolytic ring, provides essentially all 3'→5' hydrolytic exoribonuclease activity.

    Evidence In vitro reconstitution with catalytic-site mutagenesis plus in vivo phenotyping in yeast

    PMID:17173052

    Open questions at the time
    • Endonuclease activity not yet defined
    • How the core ring regulates Dis3 not addressed
  4. 2007 High

    Multiple studies established that Dis3 has functions beyond catalysis and links RNase activity to chromatin: it recognizes hypomodified tRNAi-Met in a catalysis-independent manner, and its RNase activity is required for centromeric heterochromatin silencing and kinetochore function.

    Evidence RNA-binding and TRAMP degradation assays, separation-of-function genetics, RNase mutant analysis with mad2 epistasis, and centromeric silencing reporters

    PMID:17380189 PMID:17643380

    Open questions at the time
    • Substrate-recognition domain not structurally mapped
    • Direct RNA substrate at centromeres not identified
  5. 2008 High

    Structure explained how Dis3 differs mechanistically from bacterial RNase II, revealing an occluded canonical path that forces an alternative threading route capable of duplex unwinding.

    Evidence X-ray crystallography at 2.3 Å with single-stranded RNA

    PMID:18374646

    Open questions at the time
    • Endonuclease site not captured
    • Context of the assembled exosome not represented
  6. 2009 High

    The PIN domain was defined as a bifunctional module providing both Mn2+-dependent endonuclease activity and the structural anchor for exosome association, establishing Dis3 as a two-nuclease enzyme.

    Evidence In vitro endonuclease assays with PIN metal-binding mutants, Co-IP, and in vivo pre-rRNA processing in yeast; Drosophila domain-mapping confirmed N-terminal sufficiency

    PMID:19129231 PMID:19220816

    Open questions at the time
    • Cellular substrates of the endonuclease not enumerated
    • Regulation between the two active sites unclear
  7. 2013 High

    Mechanistic regulation was clarified by showing the exosome central channel controls both Dis3 activities, and RNB cavity residues set the final product length, defining how substrate flux and trimming are governed.

    Evidence Channel-blocking and RNB-residue mutagenesis, in vitro reconstitution with thermophilic exosomes, and yeast RNA-decay readouts

    PMID:23404585 PMID:24265673

    Open questions at the time
    • Dynamics of channel-mediated allostery not resolved
    • How endonuclease substrates reach the PIN site through the ring unclear
  8. 2016 High

    The nuclear exosome structure resolved how the non-catalytic core allosterically inhibits Dis3 and how RNA paths diverge between Dis3 and Rrp6, including Dis3's distinct ability to process 3'-phosphate substrates.

    Evidence X-ray crystallography at 3.1 Å with engineered RNA plus reconstituted activity comparisons

    PMID:27818140

    Open questions at the time
    • Conformational transitions during catalysis not captured
    • Regulation in the cytoplasmic context not addressed
  9. 2015 High

    Human-cell profiling defined DIS3's nuclear substrate repertoire—PROMPTs, premature termination products, snoRNA precursors, and noncoding transcripts—and distinguished it from EXOSC10, while cytoplasmic roles emerged through LIN28B mRNA degradation controlling let-7/MYC/RAS.

    Evidence Engineered catalytic-mutant HEK293 cells with PAR-CLIP and RNA-seq; myeloma loss-of-function with mRNA stability and let-7 readouts

    PMID:25925570 PMID:26294688

    Open questions at the time
    • Nuclear vs cytoplasmic partitioning of activity not quantified
    • Direct vs indirect effects on miRNA pathway not fully separated
  10. 2019 High

    Rapid degron depletion established DIS3 and EXOSC10 as targeting genuinely distinct nuclear substrate classes in real time, and yeast work tied Dis3 to a proteostasis feedback loop via chaperone-cofactor mRNA degradation.

    Evidence Auxin-inducible degron with nuclear RNA-seq in human cells; mRNA stability, Co-IP, and ubiquitination assays in yeast

    PMID:30840897 PMID:31428776

    Open questions at the time
    • Recruitment specificity to enhancer RNAs vs PROMPTs unresolved
    • Trigger for stress-induced Dis3 ubiquitination not molecularly defined
  11. 2021 High

    DIS3 was mechanistically linked to genome architecture by showing its loss in B cells accumulates chromatin RNAs at CTCF sites, disorganizes cohesin, disrupts Igh TADs, and increases AID-driven translocations.

    Evidence Conditional Dis3 knockout mouse with Hi-C, ChIP-seq, RNA-seq, and mutation-pattern analysis

    PMID:33526923

    Open questions at the time
    • Identity of the causal chromatin RNAs not fully defined
    • Whether endo- or exonuclease activity is responsible not separated
  12. 2022 Medium

    A genome-stability mechanism was added by showing DIS3 inactivation accumulates R-loops that cause DSBs and block HR repair, sensitizing cells to PARP inhibition.

    Evidence R-loop detection, DSB and HR assays, and PARP-inhibitor sensitivity in DIS3-mutant myeloma cells with TCGA correlation

    PMID:36215697

    Open questions at the time
    • Direct vs indirect role of DIS3 in R-loop resolution unclear
    • Single-lab functional dataset
  13. 2023 High

    A developmental substrate was defined: DIS3 degrades Pou6f1 mRNA to permit the morula-to-blastocyst transition, with mRNA microinjection rescuing the knockout arrest.

    Evidence Dis3 knockout mouse, single-embryo RNA-seq, mRNA rescue, and blastomere point-mutation studies

    PMID:36724075

    Open questions at the time
    • Whether Pou6f1 is a direct substrate not biochemically confirmed
    • Breadth of developmental substrates unknown
  14. 2025 High

    Cytoplasmic, exosome-independent endonuclease function was established by showing DIS3 degrades the majority of circRNAs via PIN-domain cleavage of U-rich motifs.

    Evidence circRNA-seq after depletion, in vitro endonuclease assays on synthetic circles, exosome-independent reconstitution, and motif analysis

    PMID:39965568 PMID:40440169

    Open questions at the time
    • How DIS3 escapes exosome regulation in the cytoplasm unclear
    • U-rich motif recognition determinants not structurally defined
  15. 2026 High

    Recent work expanded DIS3 into longevity, centromere assembly, and oncogenesis: it generates tRNA halves regulating translation and dietary-restriction lifespan, promotes CENP-A loading via Dbp7/Sim3, and through the G766R variant drives plasmacytomas by accumulating on aberrant AID target RNA.

    Evidence C. elegans genetic screen and tRH/lifespan assays; fission-yeast Co-IP, CENP-A ChIP, and silencing reporters; DIS3 G766R knock-in mouse with AID mutation signatures and plasmacytoma assay

    PMID:41832173 PMID:42168172 PMID:42231506

    Open questions at the time
    • Mechanism of tRNA-half-mediated translational control not fully resolved
    • How Dis3-Dbp7 selects centromeric transcripts unclear
    • Direct chromatin-RNA substrate of G766R mutant unidentified

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how DIS3 substrate selection is partitioned between its exonuclease and endonuclease sites and between exosome-bound nuclear and stand-alone cytoplasmic pools across its many roles.
  • No unifying model of how recruitment directs a given RNA to PIN vs RNB activity
  • Determinants of nuclear-exosome vs cytoplasmic stand-alone function unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 5 GO:0003723 RNA binding 3 GO:0016787 hydrolase activity 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005730 nucleolus 1
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-73894 DNA Repair 2
Partners
DBP7EXOSC10RANRRP41RRP45SIM3SIS1SSA1
Complex memberships
RNA exosome

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Dis3 (Rrp44) is responsible for essentially all 3'→5' hydrolytic exoribonuclease activity of the yeast exosome core. Purified exosome core has Mg2+-dependent, processive, hydrolytic activity matching recombinant Dis3; a catalytically inactive Dis3 mutant abolishes exosome core activity in vitro and phenocopies exosome depletion in vivo, while mutation of the phosphorolytic site in Rrp41 has no detectable effect. In vitro reconstitution of exosome activity; catalytic site mutagenesis; in vivo RNA degradation assays in yeast Nature structural & molecular biology High 17173052
2008 Crystal structure of S. cerevisiae Rrp44 (Dis3) at 2.3 Å in complex with single-stranded RNA revealed that, unlike bacterial RNase II, the OB-fold domains are arranged to occlude the canonical RNA-binding path, forcing RNA to thread to the active site via an alternative route that can accommodate RNA duplexes for unwinding. X-ray crystallography at 2.3 Å resolution with RNA co-crystal Molecular cell High 18374646
2009 The N-terminal PIN domain of yeast Rrp44/Dis3 harbors an independent Mn2+-dependent endonuclease activity; four point mutations in the PIN domain metal-binding residues abolish this endonuclease activity. The PIN domain is also necessary and sufficient for association with the exosome core, demonstrating a dual structural and catalytic role. In vitro endonuclease assay with recombinant Rrp44 and PIN domain mutants; co-immunoprecipitation; in vivo pre-rRNA processing assays Nucleic acids research High 19129231
2007 Rrp44/Dis3 directly and specifically recognizes hypomodified tRNA(i)Met (lacking m1A58 modification) as a substrate, independently of its catalytic activity. This substrate recognition is genetically separable from Dis3 catalytic function, with recognition and catalytic activities mapping to distinct regions of the protein. Recombinant protein RNA-binding assay; in vitro degradation assay with purified TRAMP complex; yeast genetics with separation-of-function mutations Molecular cell High 17643380
2007 EM reconstruction of the yeast Rrp44-exosome complex showed that Rrp44 binds to the RNase PH domain side (bottom) of the exosome ring. The C-terminal RNase II-type active site is anchored mainly to Rrp45/Rrp43, while the N-terminal domain contacts Rrp41 and may act as a roadblock restricting RNA access to the active site, suggesting an active-site sequestration mechanism. Cryo-electron microscopy reconstruction of exosome and Rrp44-exosome complexes Proceedings of the National Academy of Sciences of the United States of America Medium 17942686
1996 Dis3 (S. cerevisiae) binds directly to Ran GTPase (and its yeast homolog Cnr1) with 1:1 stoichiometry and enhances the GEF (nucleotide-releasing) activity of RCC1 on Ran by decreasing the Km by half without changing kcat. In S. pombe, a 200 kDa Dis3 oligomer contains Spi1 (Ran) and Pim1 (RCC1). Two-hybrid interaction; direct biochemical binding assay; GEF activity assay; size-exclusion chromatography/co-fractionation The EMBO journal Medium 8896453
1991 Fission yeast Dis3 is a 110-kDa nuclear protein that forms a 250–350 kDa oligomer, is essential for growth and cell division, and is required for chromosome disjunction during mitosis. Increased Dis3 dosage suppresses the Ts+ phenotype of a cdc25 wee1 strain, placing Dis3 in the mitotic control pathway. Gene cloning, gene disruption, genetic complementation, anti-Dis3 antibody/immunolocalization, gene-dosage suppression Molecular and cellular biology Medium 1944266
2007 Ribonuclease activity of Dis3 (RNase II domain) is required for proper kinetochore formation and function in fission yeast, monitored by the Mad2 mitotic checkpoint. dis3-54 mutation reduces in vitro RNase activity and causes loss of centromeric heterochromatic silencing (at both outer repeats and central core), contributing to mitotic arrest. In vitro RNase activity assay of dis3 mutant; genetic epistasis with mad2 checkpoint mutant; inhibitor analysis; centromeric reporter gene silencing assay PloS one Medium 17380189
2013 The central channel of the exosome ring controls both the exonuclease and endonuclease activities of Dis3 in vivo and in vitro. An Rrp41 ring mutant with a partially blocked channel impairs degradation of nuclear and cytoplasmic substrates, including those dependent on Dis3 endonuclease; in vitro reconstitution with C. thermophilum exosomes confirmed the channel controls endonucleolytic activity. Rrp41 channel-blocking mutagenesis; genetic interaction with rrp6 deletion; in vitro reconstitution with recombinant C. thermophilum exosome subunits; RNA decay assays Nucleic acids research High 23404585
2016 Crystal structure of the 11-subunit nuclear exosome at 3.1 Å (with engineered dual-3'-end RNA) revealed: (1) an extended RNA path to Rrp6 through the non-catalytic core; (2) contacts between the non-catalytic core and Rrp44 that allosterically inhibit Rrp44 exoribonuclease activity; (3) structural features of the Rrp44 active site that allow degradation of 3'-phosphate RNA substrates, which are not substrates for Rrp6. X-ray crystallography at 3.1 Å; reconstituted exosome biochemical assays comparing Rrp44 vs Rrp6 activity on 3'-phosphate RNA Molecular cell High 27818140
2010 Human Dis3L1 (hDis3L1, not DIS3) localizes exclusively to the cytoplasm and associates with the exosome core (confirmed by Co-IP), whereas human DIS3 is nuclear. hDis3L1 degrades RNA via its RNB domain in an exoribonucleolytic manner; siRNA knockdown of hDis3L1 elevates poly(A)-tailed 28S rRNA degradation intermediates in the cytoplasm. Immunoaffinity purification/proteomics; co-immunoprecipitation; subcellular localization (immunofluorescence); siRNA knockdown; in vitro exoribonuclease assay The EMBO journal Medium 20531389
2015 Human DIS3, using both its exonucleolytic and endonucleolytic catalytic sites, degrades PROMPTs, premature RNA Pol II termination products, snoRNA precursors, and numerous noncoding transcripts in the nucleus. DIS3 is the main snoRNA-processing enzyme, while EXOSC10 (RRP6) controls mature snoRNA levels. DIS3 dysfunction also disrupts paraspeckle formation by causing NEAT1 short-form accumulation. Engineered HEK293 cells expressing catalytic site DIS3 mutants; PAR-CLIP; RNA-seq; transcriptome-wide profiling Genome research High 26294688
2019 Rapid depletion of DIS3 (using auxin-inducible degron) causes immediate and substantial accumulation of enhancer RNAs, PROMPTs, and products of premature cleavage and polyadenylation within 60 min. These transcripts are not affected by rapid EXOSC10 loss, demonstrating that DIS3 and EXOSC10 target distinct substrate classes in the nucleus. Auxin-inducible degron rapid depletion; nuclear RNA-seq; comparison of DIS3 vs EXOSC10 depletion substrates Cell reports High 30840897
2009 Drosophila Dis3 nuclear localization requires a C-terminal classical NLS; N-terminal domain mutants abolish association with the core exosome while only reducing binding to dRrp6. Dis3 co-precipitates importin-α3 for nuclear import. Endogenous dDis3 and dRrp6 exhibit coordinated nuclear enrichment or exclusion, suggesting they form a complex independent of the exosome core. Co-immunoprecipitation; subcellular localization of NLS/N-terminal mutants; importin-α3 pulldown in Drosophila S2 cells Traffic (Copenhagen, Denmark) Medium 19220816
2010 The Drosophila Dis3 N-terminus is sufficient for endoribonuclease activity in vitro and is necessary and sufficient for interactions with core exosome proteins. Proper N-terminal domain structure is also required for activity of the full-length enzyme. Dis3 interaction with Rrp6 and importin-α3 is independent of core exosome interaction and occurs through two distinct regions. In vitro endoribonuclease assay with deletion mutants; co-immunoprecipitation in S2 cells; subcellular localization Nucleic acids research Medium 20421210
2015 DIS3 facilitates maturation of tumor-suppressor let-7 miRNAs by degrading LIN28B mRNA in the cytoplasm. DIS3 inactivation increases LIN28B protein levels, which inhibits let-7 processing, leading to elevated translation of let-7 targets MYC and RAS. DIS3 knockdown/inactivation in myeloma cells; LIN28B mRNA stability assays; let-7 miRNA quantification; reporter and western blot for MYC/RAS Nucleic acids research Medium 25925570
2021 In DIS3-deficient mouse B cells, DNA-associated RNAs accumulate flanking CTCF-binding elements, CTCF binding decreases, cohesin localization is disorganized, and the topologically associating domain structure of the Igh locus is disrupted. DIS3 deficiency also accumulates AID-mediated asymmetric nicks, alters somatic hypermutation patterns, increases microhomology-mediated end joining, and leads to increased chromosomal translocations. Conditional Dis3 knockout mouse model; ChIP-seq for CTCF and cohesin; Hi-C; RNA-seq; mutation pattern analysis in B cells 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 the homologous recombination machinery to DSBs, impairing HR repair. DIS3-inactivated cells are sensitized to PARP inhibitors. TCGA dataset analysis; R-loop detection (S9.6 antibody); DSB assays; HR repair assay; PARP inhibitor sensitivity in DIS3-mutant myeloma patient cells The EMBO journal Medium 36215697
2025 DIS3 is responsible for degradation of the majority (>60%) of circular RNAs (circRNAs) in the cytoplasm. This degradation depends on DIS3's endonucleolytic (PIN domain) activity, is independent of the RNA exosome complex, and preferentially targets circRNAs containing U-rich motifs. Synthesized RNA circles with U-rich motifs showed decreased stability consistent with DIS3 targeting. DIS3 depletion in human cell lines with circRNA-seq; in vitro endonuclease assay with synthetic circRNA substrates; exosome-independent DIS3 activity assay; sequence motif analysis Molecular cell High 39965568
2025 Cytoplasmic DIS3 functions as a stand-alone endoribonuclease independently of the exosome core, cleaving selected circRNAs. DIS3 partially resides in the cytoplasm, and its knockdown in cell lines moderately stabilizes selected circRNAs. PIN domain endonuclease activity is the relevant catalytic activity for circRNA cleavage. Biochemical fractionation; in vitro endoribonuclease assay; DIS3 knockdown with circRNA quantification; exosome-independent reconstitution Cell reports Medium 40440169
2018 Two alternative splice isoforms of human DIS3 differ in their N-terminal PIN domain: isoform 2 (shorter PIN) has greater endonuclease activity than isoform 1 (full-length PIN) in biochemical activity assays. Multiple myeloma cells predominantly express isoform 1, whereas healthy donor and AML/CMML cells express roughly equal ratios of both isoforms. In vitro endonuclease activity assays on purified recombinant isoforms and isolated PIN domains; RT-qPCR of patient samples and cell lines The Biochemical journal Medium 29802118
2023 DIS3 ribonuclease degrades Pou6f1 mRNA during mouse pre-implantation development. In Dis3 null embryos, Pou6f1 mRNA persists, leading to POU6F1 protein accumulation that represses Nanog and Cdx2 transcription, blocking morula-to-blastocyst transition. Microinjection of Dis3 mRNA rescues the arrest phenotype. Dis3 knockout mouse model; single-embryo RNA-seq; Dis3 mRNA microinjection rescue; point mutation studies in individual blastomeres Cell reports High 36724075
2016 Drosophila Dis3 exonuclease activity is required for mitotic cell division; its absence causes mitotic delay, aneuploidy, and overcondensed chromosomes. A conserved CDK1 phosphorylation site on Dis3, when phosphorylated, inhibits Dis3's exonuclease activity but not its endonuclease activity. Modest reduction of dis3 function enhances proliferation in the presence of elevated Ras activity in flies, worms, and murine B cells. Dis3 null alleles in Drosophila; CDK1 site mutagenesis and kinase assay; cell cycle analysis; genetic interaction with ras; proliferation assay in murine B cells Genetics Medium 27029730
2019 Dis3 ribonuclease suppresses protein quality control (PQC) activity in unstressed yeast by degrading mRNAs encoding Hsp70 cofactors Sis1, Ydj1, and Fes1. Dis3 is stabilized through direct binding to Sis1 and Hsp70s Ssa1/2. Upon heat stress, loss of available Sis1 and Ssa1/2 triggers Dis3 ubiquitination and proteasomal degradation, stabilizing chaperone mRNAs. PolyQ-expanded huntingtin delays Dis3 degradation during heat stress, impairing this feedback. mRNA stability assays; co-immunoprecipitation of Dis3 with chaperones; ubiquitination assay; genetic analysis in yeast Nucleic acids research Medium 31428776
2020 Rrp44/Dis3 in S. cerevisiae localizes predominantly to the nucleus and is concentrated in the nucleolus, as are exosome core subunits Rrp41 and Rrp43, suggesting that early pre-rRNA processing is the primary function of the yeast exosome. Confocal microscopy of GFP-tagged exosome subunits in living yeast; subcellular fractionation The Journal of biological chemistry Medium 32554806
2018 In human cells, removal of the pre-rRNA 5'-ETS by-product (01/A'-A0) proceeds exclusively in the 3'→5' direction. After initiation by an unknown nuclease, DIS3 executes the ultimate degradation phase, with RRP6 acting prior to or redundantly with DIS3 in earlier phases. XRN2 5'→3' activity does not contribute to this process. siRNA knockdown of DIS3, RRP6, and XRN2 in human cells; Northern blot analysis of 5'-ETS processing intermediates RNA (New York, N.Y.) Medium 30266864
2026 DIS3 generates tRNA halves (tRHs), specifically 5'-tRH-Gln and 5'-tRH-Asp, by cleaving tRNAs in C. elegans and mammals. 5'-tRH-Gln is essential for longevity conferred by dietary restriction. In mammalian cells, DIS3 contributes to 5'-tRH-Cys generation, which delays cellular senescence by downregulating translation through ribosomal protein binding and upregulating the SKN-1/NRF transcription factor. Genetic screen in C. elegans; DIS3 loss-of-function in worms and mammalian cells; tRH profiling; lifespan assays; translation assays; ribosomal protein binding experiments Nature communications Medium 42168172
2026 The clinically relevant DIS3 G766R variant (impairs exoribonucleolytic activity) causes chromosomal translocations in B cells with aberrant AID activity signatures in a knock-in mouse model, leading to pristane-induced plasmacytomas. Mechanistically, mutant DIS3 accumulates on chromatin-bound RNA at aberrant AID target sites, promoting mutations on both DNA strands and increasing AID-dependent DSBs that drive microhomology-mediated oncogenic rearrangements during class-switch recombination. DIS3 G766R knock-in mouse model; pristane-induced plasmacytoma assay; chromatin-bound RNA analysis; AID mutation signature sequencing; IGH translocation analysis in MM patient samples Nature communications High 41832173
2026 In fission yeast, Dis3 interacts with the DEAD-box helicase Dbp7, and together they promote CENP-A loading to centromeres by interacting with the CENP-A chaperone Sim3. Dis3-Dbp7 binding to centromeric transcripts is required for Sim3 recruitment and proper CENP-A centromere loading. Visual genetic screen in fission yeast; co-immunoprecipitation of Dis3 with Dbp7 and Sim3; CENP-A ChIP; centromere silencing reporter assays; domain deletion analysis Genome biology Medium 42231506
2013 Specific residues in the RNB catalytic domain of yeast Rrp44/Dis3 determine the size of the final RNA degradation product: mutation of Y595 changes the end product from 4 to 5 nucleotides, confirming its role in stacking the RNA substrate in the catalytic cavity. Mutation of Q892 slightly increases activity in vitro. The Y595 mutant shows growth defects and impaired RNA processing in vivo. Site-directed mutagenesis of Rrp44 RNB domain; in vitro exonuclease activity assays; yeast growth assays; RNA processing analysis; molecular dynamics modeling PloS one Medium 24265673
2012 Dis3 depletion in Drosophila S2 cells and the developing fly stabilizes a largely distinct set of mRNAs compared to Rrp6 depletion, with approximately 25% of Rrp6-affected transcripts being NMD substrates; most stabilized transcripts have longer-than-average 3' UTRs. Dis3 and Rrp6 are largely functionally independent at the individual transcript level. RNAi knockdown of Drosophila exosome subunits; gene expression microarrays; bioinformatic analysis of 3' UTR length RNA (New York, N.Y.) Low 20185544

Source papers

Stage 0 corpus · 70 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 120 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 65 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 55 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
2015 The 3' to 5' Exoribonuclease DIS3: From Structure and Mechanisms to Biological Functions and Role in Human Disease. Biomolecules 48 26193331
2010 Genome-wide analysis reveals distinct substrate specificities of Rrp6, Dis3, and core exosome subunits. RNA (New York, N.Y.) 48 20185544
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 26 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
2025 Degradation of circular RNA by the ribonuclease DIS3. Molecular cell 24 39965568
2015 The 3'-5' exoribonuclease Dis3 regulates the expression of specific microRNAs in Drosophila wing imaginal discs. RNA biology 23 25892215
2022 DIS3 mutations in multiple myeloma impact the transcriptional signature and clinical outcome. Haematologica 21 33951891
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
2022 Loss of ribonuclease DIS3 hampers genome integrity in myeloma by disrupting DNA:RNA hybrid metabolism. The EMBO journal 19 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 14 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
2023 Trypanosoma brucei RRP44: a versatile enzyme for processing structured and non-structured RNA substrates. Nucleic acids research 7 36583334
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
2025 Cytoplasmic DIS3 is an exosome-independent endoribonuclease with catalytic activity toward circular RNAs. Cell reports 5 40440169
2023 DIS3 Variants are Associated With Primary Ovarian Insufficiency: Importance of Transcription/Translation in Oogenesis. The Journal of clinical endocrinology and metabolism 4 36869713
2025 Functional characterization of human recessive DIS3 variants in premature ovarian insufficiency†. Biology of reproduction 3 39400047
2023 Dissecting Trypanosoma brucei RRP44 function in the maturation of segmented ribosomal RNA using a regulated genetic complementation system. Nucleic acids research 3 36610751
2012 Dis3- and exosome subunit-responsive 3' mRNA instability elements. Biochemical and biophysical research communications 3 22668878
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
2026 Ribonuclease DIS3 delays aging and senescence by generating tRNA halves. Nature communications 0 42168172
2026 Investigation of the Relationship Between Ovine Selection Signature DIS3 Like 3'-5' Exoribonuclease 2 (DIS3L2) Gene and Weaning Weight and Average Daily Gain Until Weaning in Lambs. Animal genetics 0 42229879
2026 Dbp7 interacts with RNA exosome component Dis3 to mediate CENP-A loading to centromeres. Genome biology 0 42231506
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

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