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Showing MTREX — SKIV2L2 is a alias.

MTREX

Exosome RNA helicase MTR4 · UniProt P42285

Length
1042 aa
Mass
117.8 kDa
Annotated
2026-06-10
53 papers in source corpus 35 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MTREX (MTR4/SKIV2L2) is a conserved DExH-box RNA helicase that serves as the principal helicase cofactor of the nuclear RNA exosome, unwinding structured RNA substrates and channeling them for 3'-to-5' degradation (PMID:20566885, PMID:29906447). Its catalytic core couples ATP-dependent unwinding to substrate handoff, while an inserted arch/KOW domain functions both as a substrate-presentation element required for 5.8S rRNA processing and as a versatile recruitment platform that recognizes short arch-interacting motifs (AIMs) in diverse adaptors including Nop53, NVL, ZCCHC8, and PICT1, with arch-RNA contacts further promoting a closed, unwinding-competent conformation (PMID:20512111, PMID:28883156, PMID:31358741, PMID:35380691, PMID:36403484). MTR4 is delivered to the exosome through a composite Rrp6-Rrp47 surface and is tethered to the core by Mpp6, which extends the RNA trajectory into the central channel toward the DIS3 active site, displacing EXOSC10 to commit RNA to degradation (PMID:25319414, PMID:28877463, PMID:28742025, PMID:29906447). Within the TRAMP complex MTR4 partners with Trf4/Air2 (Cid14), whose polyadenylation activity and N-terminal contacts stimulate unwinding of otherwise refractory substrates, while in mammals it nucleates the NEXT complex through ZCCHC8, which stimulates its helicase and ATPase activities, and a distinct ZFC3H1-containing complex; its activity is held in check by NRDE2, which locks MTR4 in a closed conformation in nuclear speckles (PMID:22532666, PMID:29844170, PMID:28733371, PMID:30842217, PMID:40519184). Through these activities MTR4 surveils a broad RNA repertoire—prematurely terminated and antisense transcripts, replication-dependent histone mRNAs, snRNAs, 3'-extended read-through transcripts, and maternal RNAs—and is required for rRNA processing, cell-cycle progression, oocyte growth, and meiotic initiation in germ cells (PMID:28733371, PMID:39419981, PMID:40097464, PMID:28351885, PMID:39378876). MTR4 protein levels are controlled under methionine restriction by SYVN1-mediated ubiquitination, coupling RNA surveillance to nuclear mRNA export and metabolic signaling (PMID:33859984).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1995 Low

    Established the molecular identity of human MTREX as an RNA helicase, defining its catalytic potential before any functional role was known.

    Evidence Molecular cloning and baculovirus expression identifying DEVH-box helicase motifs and demonstrating ATPase activity in vitro

    PMID:7610041

    Open questions at the time
    • No helicase or unwinding activity demonstrated
    • No interaction partners or cellular role established
  2. 2010 High

    Crystal structures resolved how MTR4 is built—a DExH ATPase core with an inserted arch/KOW domain—answering how the enzyme both unwinds RNA and presents substrates while serving as a TRAMP protein-binding platform.

    Evidence X-ray crystallography of S. cerevisiae Mtr4 with in vitro RNA binding, helicase assays, and in vivo rRNA processing assays

    PMID:20512111 PMID:20566885

    Open questions at the time
    • AIM-based adaptor recognition not yet defined
    • Exosome-docking interface not structurally resolved
    • Catalytic cycle of unwinding not mechanistically dissected
  3. 2012 High

    Resolved how TRAMP enhances MTR4 function, showing Trf4/Air2 stimulate unwinding independently of ongoing polyadenylation while adenylation provides a minimal binding site that enables decay of refractory substrates.

    Evidence Reconstituted TRAMP with in vitro RNA unwinding and polyadenylation assays

    PMID:22532666

    Open questions at the time
    • Structural basis of helicase stimulation not resolved
    • Generalization to mammalian adaptors not tested
  4. 2014 High

    Defined the route by which MTR4 docks onto the exosome (composite Rrp6-Rrp47 surface) and revealed that the arch domain contributes to unwinding beyond substrate presentation.

    Evidence X-ray crystallography, in vitro binding, ratchet-helix and arch mutagenesis, and in vivo growth assays in yeast

    PMID:25319414 PMID:25414331

    Open questions at the time
    • How RNA is physically channeled into the core not yet shown
    • Mammalian conservation of the recruitment surface untested
  5. 2017 High

    Established the AIM as the general recruitment grammar of the arch domain and showed Mpp6 tethers MTR4 to the core to extend RNA into the central channel, building a structural mechanism for substrate channeling.

    Evidence Crystallography and NMR of Mtr4 KOW-AIM (Nop53) recognition plus reconstituted Mpp6-exosome channeling and decay assays

    PMID:28742025 PMID:28877463 PMID:28883156

    Open questions at the time
    • How distinct adaptors achieve substrate specificity not fully resolved
    • Dynamics of channeling during processive degradation not captured
  6. 2017 High

    Identified MTR4 as the rate-limiting exosome cofactor in human cells, partnering with ZFC3H1 independent of NEXT, whose loss exports prematurely terminated transcripts that repress translation, and linked exosome-coupled MTR4 activity to histone mRNA turnover, cell-cycle progression, and Ig-locus mutation patterning.

    Evidence siRNA knockdown, RNA fractionation, reciprocal Co-IP, ribosome profiling, cell-cycle analysis, and proximity ligation across multiple cell systems

    PMID:28351885 PMID:28431250 PMID:28733371

    Open questions at the time
    • Composition and regulation of the ZFC3H1 complex incompletely defined
    • Direct mechanism of strand-specific mutation patterning unclear
  7. 2018 High

    Captured the human MTR4-exosome holocomplex on a stalled substrate, showing MTR4 caps the core, feeds RNA to DIS3, and displaces EXOSC10 to commit RNA to degradation, and defined how ZCCHC8 stimulates MTR4 within NEXT.

    Evidence Cryo-EM at 3.45 Å with multi-organism reconstitution and unwinding/degradation assays; ZCCHC8 crystallography with helicase/ATPase assays

    PMID:29844170 PMID:29906447

    Open questions at the time
    • Conformational transitions between recruitment and degradation states not time-resolved
    • Switch between competing adaptors in vivo not defined
  8. 2019 High

    Resolved how MTR4 is regulated—NRDE2 locks it in a closed, inactive conformation in nuclear speckles to protect export-bound mRNA—and showed mutually exclusive AIM-based recruitment of NVL and ZCCHC8 diversifies its targeting.

    Evidence Co-IP, NMR, structural analysis, mutagenesis, fractionation, and stem-cell self-renewal assays

    PMID:30842217 PMID:31358741

    Open questions at the time
    • Signals controlling NRDE2-MTR4 release not identified
    • How adaptor choice is decided in vivo unknown
  9. 2021 Medium

    Connected MTR4 abundance to metabolic state, showing SYVN1-dependent ubiquitination under methionine restriction lowers MTR4 and licenses MAT2A mRNA export, and identified hnRNPH1 as an RNA-independent partner directing NEAT1v2 decay.

    Evidence Co-IP, ubiquitination assays, knockdown, and nuclear-cytoplasmic fractionation

    PMID:33859984 PMID:34470577

    Open questions at the time
    • Single-lab observations without independent replication
    • Direct ubiquitination sites on MTR4 not mapped
  10. 2022 Medium

    Refined the biochemistry of MTR4 unwinding by mapping arch-RNA contacts that drive a closed conformation, defined the C-terminal SLYΦ motif coordinating exosome interaction, and added PICT1 as a step-specific rRNA-processing adaptor.

    Evidence HDX-MS with RNA affinity/unwinding assays, C-terminal mutagenesis with yeast genetic epistasis, and PICT1 AIM-mutant rRNA processing assays

    PMID:35380691 PMID:36403484 PMID:38085597

    Open questions at the time
    • Conformational landscape during processive unwinding incomplete
    • Mostly single-lab biochemical observations
  11. 2024 Medium

    Demonstrated developmental requirements for MTR4-dependent surveillance, showing it is indispensable for oocyte growth and chromatin reorganization and that it surveils 3'-extended read-through transcripts whose aberrant proteins form condensates.

    Evidence Oocyte-specific conditional knockout with RNA-seq and chromatin analysis; Co-IP, long-read RNA-seq, and condensate imaging for hnRNPK-MTR4 3XT surveillance

    PMID:39378876 PMID:39419981

    Open questions at the time
    • Direct link between RNA surveillance defects and chromatin phenotypes not mechanistically dissected
    • Breadth of 3XT substrate repertoire not fully defined
  12. 2025 Medium

    Extended MTR4 biology to germ-cell meiotic initiation, nucleolar retention of the exosome, and metabolic mRNA-export control, while refining TRAMP-driven helicase activation and the role of intrinsically disordered adaptor regions.

    Evidence Germ-cell conditional KO with splicing analysis, nucleolar imaging/proteomics under MTR4 depletion, reconstituted S. pombe TRAMP helicase assays, HDX-MS of TRAMP, and KMT2B methylation/export assays

    PMID:39752526 PMID:40097464 PMID:40519184 PMID:40651665 PMID:41428109

    Open questions at the time
    • How MTR4 enforces nucleolar exosome localization mechanistically unclear
    • KMT2B methylation evidence is low-confidence and single-lab
    • In vivo relevance of S. pombe helicase decoupling to mammals untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MTR4 conformational switching, adaptor selection, and post-translational control are integrated in real time to choose between RNA degradation, export licensing, and chromatin/loop-extrusion functions remains unresolved.
  • No time-resolved structural account of the recruitment-to-degradation cycle
  • Signals governing adaptor exchange and NRDE2 release unknown
  • Chromatin/loop-extrusion role rests on a single preprint

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0140098 catalytic activity, acting on RNA 4 GO:0140657 ATP-dependent activity 4 GO:0016787 hydrolase activity 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005634 nucleus 4 GO:0005730 nucleolus 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
HNRNPKMPP6NRDE2NVLPICT1RRP6ZCCHC8ZFC3H1
Complex memberships
NEXTTRAMPZFC3H1-MTR4 (PAXT-related) complexnuclear RNA exosome

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 Crystal structure of S. cerevisiae Mtr4 at 2.9 Å resolution reveals a central DExH ATPase core with an inserted stalk/KOW (arch) domain; the KOW domain binds tRNA in vitro, suggesting it presents RNA substrates to the helicase core; interaction with Trf4-Air2 is mediated by the DExH core, not the arch; the DExH core functions as an RNA helicase and protein-binding platform within TRAMP. X-ray crystallography (2.9 Å), in vitro RNA binding assay, in vitro helicase assay Proceedings of the National Academy of Sciences of the United States of America High 20566885
2010 Crystal structure of Mtr4 reveals a novel arch domain specific to Mtr4 and Ski2; in vivo and in vitro analyses demonstrate the arch domain is required for proper 5.8S rRNA processing, functioning independently of canonical helicase activity; conserved residues at the putative RNA exit site highlight an interface with the exosome. X-ray crystallography, in vivo growth/processing assays, in vitro biochemical assays The EMBO journal High 20512111
2012 TRAMP complex robustly unwinds RNA duplexes; Trf4p/Air2p significantly stimulates Mtr4p unwinding activity independently of ongoing polyadenylation; polyadenylation by TRAMP enables unwinding of substrates that Mtr4p alone cannot unwind; optimal unwinding requires substrates with a minimal Mtr4p binding site comprised of adenylates. In vitro RNA unwinding assay, in vitro polyadenylation assay, reconstituted TRAMP complex Proceedings of the National Academy of Sciences of the United States of America High 22532666
2011 Air1/2 zinc knuckles 4 and 5 and a conserved IWRXY motif in the ZnK4-5 linker are critical for Trf4 interaction and TRAMP complex integrity; Air1 ZnK4 is required for degradation of CUTs; the human orthologue hZCCHC7 (containing the IWRXY motif) localizes to the nucleolus and interacts with mammalian Trf4 orthologues PAPD5 and PAPD7. Random mutagenesis, in vivo CUT accumulation assays, co-immunoprecipitation, subcellular localization The Journal of biological chemistry Medium 21878619
2014 Rrp6 and Rrp47 form a highly intertwined structural unit; they synergize to create a composite conserved surface groove that binds the N-terminus of Mtr4; mutations at the Rrp6-Mtr4 interface disrupt their interaction and inhibit growth, establishing Rrp6-Rrp47 as the platform recruiting Mtr4 to the exosome in yeast. X-ray crystallography, in vitro binding assays, site-directed mutagenesis, in vivo growth assays The EMBO journal High 25319414
2014 The ratchet helix of Mtr4 modulates helicase activity; mutations along the ratchet helix alter in vitro unwinding activity and cause slow growth in vivo; combining arch domain deletion with ratchet helix mutations abolishes helicase activity and causes a lethal phenotype, revealing that the arch domain plays a previously unrecognized role in RNA unwinding. Site-directed mutagenesis, in vitro helicase/unwinding assay, in vivo growth assay Nucleic acids research High 25414331
2017 Mtr4 interacts directly with the preribosomal protein Nop53 via an arch-interacting motif (AIM); crystal structure at 3.2 Å shows the KOW domain of Mtr4 recognizes the AIM sequence through hydrophobic and electrostatic interactions; NMR shows the KOW domain can simultaneously bind an AIM-containing protein and structured RNA at adjacent surfaces; AIM-interacting residues are conserved in Mtr4 but absent in Ski2, explaining specificity. X-ray crystallography (3.2 Å), NMR, in vitro binding assays RNA (New York, N.Y.) High 28883156
2017 Mpp6 binds the nine-subunit exosome core directly and independently; Mtr4 binding to the exosome in vitro requires both Rrp6 and Rrp47; Mpp6 is required for Mtr4 to extend the RNA trajectory entering the exosome core, promoting channeling of substrates from the nuclear helicase to the processive RNase. X-ray crystallography (3.2 Å), in vitro binding assays, RNA channeling/degradation assays Cell reports High 28877463
2017 Rrp47 and Mpp6 each stimulate exosome-mediated RNA decay; Mpp6-exosomes can recruit Mtr4; maximal Mtr4-dependent decay requires both Mpp6 and Rrp47; 3.3 Å structure of 12-subunit nuclear Mpp6-exosome bound to RNA shows central Mpp6 region bound to the exosome core, positioning its Mtr4 recruitment domain next to Rrp6 and the exosome central channel. Biochemical reconstitution, RNA decay assays, X-ray crystallography (3.3 Å), genetic analysis eLife High 28742025
2017 MTR4 knockdown but not knockdown of other NEXT subunits causes accumulation of prematurely terminated RNAs (ptRNAs) and upstream antisense RNAs (uaRNAs); MTR4 forms a distinct complex with zinc finger protein ZFC3H1 independent of NEXT; knockdown of either MTR4 or ZFC3H1 causes accumulation and cytoplasmic export of ptRNAs/uaRNAs, which associate with ribosomes and cause global translational repression. siRNA knockdown, RNA fractionation, co-immunoprecipitation, ribosome profiling Genes & development High 28733371
2017 MTR4 (and senataxin) physically proximal in the nucleus; the coupled activities of RNA helicase Mtr4 with the noncoding RNA processing function of RNA exosome determine the strand-specific distribution of sense and antisense strand DNA mutations at the immunoglobulin heavy chain locus in B cells. Proximity ligation, genetic perturbation, deep sequencing of mutation patterns Cell Medium 28431250
2018 Cryo-EM structure at 3.45 Å of human MTR4-containing nuclear RNA exosome loaded with a stalled RNA substrate: MTR4 sits atop the non-catalytic core with RNA captured in the central channel reaching the DIS3 active site; MPP6 tethers MTR4 to the exosome through contacts to the RecA domains of MTR4; EXOSC10 is displaced by RNA-engaged MTR4, suggesting competition ensures RNA commitment to degradation; reconstituted 14-subunit Mtr4-containing exosomes from S. cerevisiae, S. pombe, and human unwind structured substrates to promote degradation. Cryo-EM (3.45 Å), reconstitution, in vitro unwinding/degradation assay Cell High 29906447
2018 ZCCHC8 interacts with MTR4 via a bipartite interaction; a crystal structure shows the ZCCHC8 C-terminal domain binds the helicase core in a manner distinct from yeast cofactors Trf4p/Air2p; ZCCHC8 C-terminal domain stimulates MTR4 helicase and ATPase activities; uridine-rich substrates are preferred by NEXT but optimal activity requires a polyadenylated 3' end. X-ray crystallography, in vitro helicase/ATPase assay, binding assays Proceedings of the National Academy of Sciences of the United States of America High 29844170
2019 Human MTR4 recruits nuclear adaptors NVL (ribosome processing) and ZCCHC8 (snRNA decay) via short linear arch-interacting motifs (AIM) in their unstructured regions that bind the MTR4 arch domain in a mutually exclusive manner; these sequences diverged from the canonical AIM of yeast rRNA processing factors, demonstrating versatility of the MTR4 arch domain as a recruitment platform. Co-immunoprecipitation, peptide binding assays, NMR, mutagenesis Nature communications High 31358741
2019 NRDE2 forms a 1:1 complex with MTR4 via a conserved MTR4-interacting domain (MID); NRDE2 mainly localizes in nuclear speckles; NRDE2 inhibits MTR4 recruitment and RNA degradation in nuclear speckles, ensuring efficient mRNA nuclear export; structurally, NRDE2 locks MTR4 in a closed conformation and inhibits MTR4 interaction with the exosome, CBC, and ZFC3H1; MID deletion causes loss of self-renewal in mouse embryonic stem cells. Co-immunoprecipitation, structural analysis, siRNA knockdown, subcellular fractionation, stem cell self-renewal assay Genes & development High 30842217
2006 NVL2 (DOB1/MTR4 human homolog context: NVL2 interacts with DOB1/MTREX) associates with pre-ribosomal particles; NVL2 interacts with DOB1 (human MTREX/MTR4) via yeast two-hybrid and co-immunoprecipitation; dominant-negative NVL2 causes DOB1 to remain associated with nuclear pre-ribosomal particles, suggesting NVL2 regulates DOB1 association/dissociation with pre-ribosomes as a molecular chaperone. Yeast two-hybrid, co-immunoprecipitation, dominant-negative overexpression, subcellular fractionation Biochemical and biophysical research communications Medium 16782053
2015 AAA-ATPase NVL2 acts on the MTR4-exosome complex to stimulate dissociation of WDR74 (a WD repeat protein with similarity to yeast Nsa1) in an ATPase-dependent manner; WDR74 co-localizes with NVL2 in the nucleolus; knockdown of WDR74 decreases 60S ribosome levels, placing this NVL2-regulated MTR4-WDR74 interaction in the ribosome biogenesis pathway. Proteomic screen, co-immunoprecipitation, ATPase mutant analysis, siRNA knockdown, ribosome profiling Biochemical and biophysical research communications Medium 26456651
2020 MTR4 ensures correct alternative splicing of pre-mRNAs of critical glycolytic genes GLUT1 and PKM2; c-Myc binds the MTR4 promoter and drives MTR4 expression in HCC cells, placing MTR4 as a mediator of c-Myc function in cancer metabolism. siRNA knockdown, RT-PCR for alternative splicing, ChIP for c-Myc promoter binding, metabolic assays Nature communications Medium 32024842
2021 SYVN1 is the E3 ubiquitin ligase responsible for ubiquitination of MTR4 under methionine restriction, leading to reduced MTR4 protein levels; reduced MTR4 promotes nuclear export of MAT2A mRNA, increasing MAT2A protein expression. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, nuclear-cytoplasmic fractionation Frontiers in cell and developmental biology Medium 33859984
2021 hnRNPH1 associates with MTR4 in an RNA-independent manner; hnRNPH1 localizes in nuclear speckles; the hnRNPH1-MTR4 complex controls degradation of NEAT1v2 lncRNA and thereby regulates IL8 mRNA expression. Co-immunoprecipitation (RNA-independent), siRNA knockdown, subcellular localization, RNA quantification RNA biology Medium 34470577
2022 Hydrogen-deuterium exchange MS identifies RNA interactions within the Mtr4 helicase core consistent with existing structures, and novel RNA interactions within the KOW/fist region of the arch domain that vary depending on RNA structure and length; these arch-RNA interactions are important for RNA unwinding and drive Mtr4 to adopt a closed conformation with reduced arch dynamics and intra-domain contacts between the fist and helicase core. Hydrogen-deuterium exchange mass spectrometry (HDX-MS), in vitro RNA affinity assays, in vitro unwinding assays Nucleic acids research Medium 35380691
2022 APE1 interacts with MTR4; the interaction is stimulated by cisplatin and 5-FU treatment through lysine residues in the APE1 N-terminal region and is partially mediated by nucleic acids; both APE1 and MTR4 depletion lead to R-loop formation and activation of ATM-p53-p21 DNA damage response; APE1 functions in damaged RNA elimination in a MTR4-independent manner. Co-immunoprecipitation, siRNA knockdown, R-loop detection, DNA damage response assays The FEBS journal Medium 36310106
2022 PICT1 (mammalian Nop53 orthologue) interacts with MTR4 and the exosome in an AIM-dependent manner; PICT1 is involved in two distinct pre-rRNA processing steps during 60S ribosome biogenesis (early cleavage of 32S rRNA and late maturation of 12S to 5.8S rRNA); MTR4/exosome recruitment via the AIM sequence is required only for the late processing step. Co-immunoprecipitation, AIM mutant overexpression, siRNA knockdown, Northern blot/rRNA processing assays Biochemical and biophysical research communications Medium 36403484
2023 Conserved SLYΦ sequence at the Mtr4 C-terminal tail is critical for helicase function; mutations in the C-terminus reduce RNA unwinding activity in vitro and impair RNA degradation by exonuclease Rrp44 in vitro; C-terminal mutations combined with partial exosome defects produce synthetic slow growth in S. cerevisiae, indicating the C-terminus coordinates Mtr4-exosome interactions. Site-directed mutagenesis, in vitro helicase assay, in vitro degradation assay, yeast genetic epistasis Biochemistry Medium 38085597
2023 A multiple myeloma patient missense mutation in EXOSC2 (M40T) maps to a residue that contacts MTR4; the yeast equivalent rrp4-M68T shows accumulation of RNA exosome target RNAs, drug sensitivity, and negative genetic interactions with specific mtr4 mutants; Rrp4 M68T shows decreased binding to Mtr4 biochemically, establishing direct structural importance of this interface for Mtr4-exosome interaction in vivo. Yeast genetics (epistasis), biochemical interaction assay, RNA accumulation assay G3 (Bethesda, Md.) Medium 36861343
2024 MTR4 is indispensable for oocyte growth; MTR4-dependent RNA surveillance ensures normal post-transcriptional processing of maternal RNAs, their nuclear export, and cytoplasmic accumulation; Mtr4 knockout oocytes fail to grow to normal size; MTR4-dependent RNA surveillance is required for maintaining nuclear H3K4me3 and chromatin reorganization necessary for nucleolus-like structure formation in oocytes. Conditional knockout (oocyte-specific), RNA sequencing, immunostaining, chromatin analysis Developmental cell Medium 39378876
2024 MTR4 associates with hnRNPK; the MTR4-hnRNPK complex surveils 3' eXtended Transcripts (3XTs)—intronic polyadenylated transcripts generated by transcriptional read-through; MTR4 destabilizes 3XTs with multiple exons via the hnRNPK-MTR4-RNA exosome pathway; aberrant protein translated from KCTD13 3XT forms condensates (KeXT bodies) that are suppressed by this surveillance pathway. Co-immunoprecipitation, long-read RNA sequencing, siRNA knockdown, condensate imaging Nature communications Medium 39419981
2025 MTR4, the central cofactor of the nuclear RNA exosome, is essential for embryogenesis and spermatogenesis; germ cell-specific Mtr4 knockout causes male infertility with a specific defect in meiotic initiation; MTR4/exosome represses meiotic genes through RNA degradation while ensuring expression of mitotic genes; replication-dependent histone mRNAs and polyadenylated retrotransposon RNAs are MTR4/exosome targets in germ cells; MTR4 regulates alternative splicing of meiotic genes. Conditional knockout (germ cell-specific), RNA sequencing, alternative splicing analysis, Northern blot Nature communications Medium 40097464
2025 MTR4 regulates the localization of the RNA exosome within the nucleus; depletion of MTR4 causes translocation of RNA exosome subunits from the nucleolus to the nucleoplasm; this regulation is specific to MTR4 and does not depend on other cofactors of the TRAMP, PAXT, or NEXT complexes; actinomycin D-induced transcription inhibition also induces exosome translocation, likely through reduction of nucleolar MTR4 levels. Immunostaining, fluorescence tagging, siRNA knockdown, nucleolar quantitative proteomics Molecular & cellular proteomics : MCP Medium 40651665
2025 TRAMP assembly constrains RNA-recognition motifs peripheral to catalytic sites, including the Mtr4 Arch and Air2 zinc knuckles 1-3; tRNA binding by TRAMP differs from individual subunits with reduced binding on the Mtr4 Fist and RecA2 domains and increased binding on Air2 zinc knuckles 2 and 3, consistent with competition between RNA-binding sites driving tRNA transfer between TRAMP catalytic sites. Hydrogen-deuterium exchange mass spectrometry (HDX-MS), thermodynamic assays, in vitro functional assays Proceedings of the National Academy of Sciences of the United States of America Medium 39752526
2025 In S. pombe, Mtr4 retains RNA-stimulated ATPase activity but cannot unwind RNA substrates alone; TRAMP formation overcomes this helicase decoupling; activation of helicase activity is accomplished by interactions with multiple regions of the intrinsically disordered N-terminus of Cid14 (S. pombe Trf4 homologue), proposing that Mtr4 adaptor complexes regulate unwinding by coordinating interdomain interactions within the helicase core. In vitro ATPase assay, in vitro helicase/unwinding assay, reconstituted TRAMP, deletion analysis of Cid14 N-terminus Biochemistry Medium 40519184
2025 MTR4 methylation by KMT2B under methionine starvation promotes its ubiquitin-mediated degradation, which facilitates nuclear export of SLC1A5 (amino acid transporter) mRNA, leading to increased amino acid uptake and mTORC1 activation in glioma cells. Western blotting, qRT-PCR, nuclear-cytoplasmic fractionation, co-immunoprecipitation, methyltransferase identification Amino acids Low 41428109
2025 MTR4 (MTREX/SKIV2L2) modulates 3D long-range enhancer-promoter contacts; depletion of MTR4 causes accumulation of eRNAs and PROMPTs, increased cohesin levels at sites of ncRNA accumulation, increased contacts at anchor points and decreased intra-loop contacts, suggesting MTR4 facilitates cohesin-mediated loop extrusion. Chromatin conformation capture (Hi-C/3C), ChIP-seq for cohesin, RNA-seq, siRNA knockdown, chromatin recruitment mapping bioRxivpreprint Low
2017 SKIV2L2/MTR4 depletion in murine cell lines causes defective G2/M progression and accumulation of mitotic cells; knockdown leads to accumulation of replication-dependent histone mRNAs, identifying these as nuclear exosome substrates dependent on SKIV2L2. siRNA knockdown, cell-cycle analysis (propidium iodide), RNA quantification RNA (New York, N.Y.) Medium 28351885
2011 SKIV2L2 protein is predominantly localized to nuclei of round spermatids in mouse testis; SKIV2L2 has RNA-binding and ATPase activities in vitro. Proteome analysis, in situ hybridization, immunolocalization, in vitro ATPase and RNA binding assays The Journal of reproduction and development Low 21467735
1995 Human SKI2W (SKIV2L2/MTREX) encodes a protein with RNA helicase motifs (DEVH box) and a leucine zipper; fusion protein expressed in insect cells has ATPase activity. Molecular cloning, baculovirus expression, ATPase assay Nucleic acids research Low 7610041

Source papers

Stage 0 corpus · 53 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Mtr4-like protein coordinates nuclear RNA processing for heterochromatin assembly and for telomere maintenance. Cell 158 24210919
2010 Structural analysis reveals the characteristic features of Mtr4, a DExH helicase involved in nuclear RNA processing and surveillance. Proceedings of the National Academy of Sciences of the United States of America 123 20566885
2018 Helicase-Dependent RNA Decay Illuminated by a Cryo-EM Structure of a Human Nuclear RNA Exosome-MTR4 Complex. Cell 121 29906447
2017 An Mtr4/ZFC3H1 complex facilitates turnover of unstable nuclear RNAs to prevent their cytoplasmic transport and global translational repression. Genes & development 113 28733371
2010 The crystal structure of Mtr4 reveals a novel arch domain required for rRNA processing. The EMBO journal 101 20512111
2014 The exosome-binding factors Rrp6 and Rrp47 form a composite surface for recruiting the Mtr4 helicase. The EMBO journal 94 25319414
2020 MTR4 drives liver tumorigenesis by promoting cancer metabolic switch through alternative splicing. Nature communications 81 32024842
2012 RNA unwinding by the Trf4/Air2/Mtr4 polyadenylation (TRAMP) complex. Proceedings of the National Academy of Sciences of the United States of America 62 22532666
2011 Air1 zinc knuckles 4 and 5 and a conserved IWRXY motif are critical for the function and integrity of the Trf4/5-Air1/2-Mtr4 polyadenylation (TRAMP) RNA quality control complex. The Journal of biological chemistry 61 21878619
2018 Structural basis for MTR4-ZCCHC8 interactions that stimulate the MTR4 helicase in the nuclear exosome-targeting complex. Proceedings of the National Academy of Sciences of the United States of America 57 29844170
2017 Nuclear Proximity of Mtr4 to RNA Exosome Restricts DNA Mutational Asymmetry. Cell 56 28431250
2017 Structure and reconstitution of yeast Mpp6-nuclear exosome complexes reveals that Mpp6 stimulates RNA decay and recruits the Mtr4 helicase. eLife 50 28742025
1995 Human helicase gene SKI2W in the HLA class III region exhibits striking structural similarities to the yeast antiviral gene SKI2 and to the human gene KIAA0052: emergence of a new gene family. Nucleic acids research 50 7610041
2017 Mpp6 Incorporation in the Nuclear Exosome Contributes to RNA Channeling through the Mtr4 Helicase. Cell reports 48 28877463
2019 The MTR4 helicase recruits nuclear adaptors of the human RNA exosome using distinct arch-interacting motifs. Nature communications 45 31358741
2019 NRDE2 negatively regulates exosome functions by inhibiting MTR4 recruitment and exosome interaction. Genes & development 44 30842217
2017 Structural insights into the interaction of the nuclear exosome helicase Mtr4 with the preribosomal protein Nop53. RNA (New York, N.Y.) 37 28883156
2007 Mutations in gfpt1 and skiv2l2 cause distinct stage-specific defects in larval melanocyte regeneration in zebrafish. PLoS genetics 35 17542649
2007 Trypanosome MTR4 is involved in rRNA processing. Nucleic acids research 33 17940093
2006 The AAA-ATPase NVL2 is a component of pre-ribosomal particles that interacts with the DExD/H-box RNA helicase DOB1. Biochemical and biophysical research communications 33 16782053
2014 The Mtr4 ratchet helix and arch domain both function to promote RNA unwinding. Nucleic acids research 32 25414331
1994 HLA-DOB1 "low-resolution' typing by PCR amplification with sequence-specific primers (PCR-SSP). European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics 31 9098454
2013 Cotranscriptional recruitment of RNA exosome cofactors Rrp47p and Mpp6p and two distinct Trf-Air-Mtr4 polyadenylation (TRAMP) complexes assists the exonuclease Rrp6p in the targeting and degradation of an aberrant messenger ribonucleoprotein particle (mRNP) in yeast. The Journal of biological chemistry 29 24047896
1999 HLA DOA1 and DOB1 loci in Honduran women with cervical dysplasia and invasive cervical carcinoma and their relationship to human papillomavirus infection. Human biology 25 10380373
2015 AAA-ATPase NVL2 acts on MTR4-exosome complex to dissociate the nucleolar protein WDR74. Biochemical and biophysical research communications 20 26456651
2012 Genetic interactions suggest multiple distinct roles of the arch and core helicase domains of Mtr4 in Rrp6 and exosome function. Nucleic acids research 18 23143101
2021 Mtr4 RNA helicase structures and interactions. Biological chemistry 17 33857361
2021 SYVN1-MTR4-MAT2A Signaling Axis Regulates Methionine Metabolism in Glioma Cells. Frontiers in cell and developmental biology 14 33859984
2021 hnRNPH1-MTR4 complex-mediated regulation of NEAT1v2 stability is critical for IL8 expression. RNA biology 12 34470577
2022 APE1 interacts with the nuclear exosome complex protein MTR4 and is involved in cisplatin- and 5-fluorouracil-induced RNA damage response. The FEBS journal 10 36310106
2024 RNA surveillance by the RNA helicase MTR4 determines volume of mouse oocytes. Developmental cell 8 39378876
2023 The RNA helicases Dbp2 and Mtr4 regulate the expression of Xrn1-sensitive long non-coding RNAs in yeast. Frontiers in RNA research 8 37667796
2022 Hydrogen-deuterium exchange mass spectrometry of Mtr4 with diverse RNAs reveals substrate-dependent dynamics and interfaces in the arch. Nucleic acids research 8 35380691
2017 Loss of the RNA helicase SKIV2L2 impairs mitotic progression and replication-dependent histone mRNA turnover in murine cell lines. RNA (New York, N.Y.) 8 28351885
2011 Localization of a novel RNA-binding protein, SKIV2L2, to the nucleus in the round spermatids of mice. The Journal of reproduction and development 8 21467735
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
2022 Using hydrogen-deuterium exchange mass spectrometry to characterize Mtr4 interactions with RNA. Methods in enzymology 7 35965017
2021 Interactome analysis of the Tudor domain-containing protein SPF30 which associates with the MTR4-exosome RNA-decay machinery under the regulation of AAA-ATPase NVL2. The international journal of biochemistry & cell biology 7 33422691
2020 Exploration of Salmonella effector mutant strains on MTR4 and RRP6 degradation. Bioscience trends 5 32350160
2016 Mutations in Mtr4 Structural Domains Reveal Their Important Role in Regulating tRNAiMet Turnover in Saccharomyces cerevisiae and Mtr4p Enzymatic Activities In Vitro. PloS one 5 26820724
2014 Certain adenylated non-coding RNAs, including 5' leader sequences of primary microRNA transcripts, accumulate in mouse cells following depletion of the RNA helicase MTR4. PloS one 5 24926684
2023 In vivo characterization of the critical interaction between the RNA exosome and the essential RNA helicase Mtr4 in Saccharomyces cerevisiae. G3 (Bethesda, Md.) 4 36861343
2022 Purification and characterization of Mtr4 and TRAMP from S. cerevisiae. Methods in enzymology 3 35965015
2022 MTR4 adaptor PICT1 functions in two distinct steps during pre-rRNA processing. Biochemical and biophysical research communications 3 36403484
2025 TRAMP assembly alters the conformation and RNA binding of Mtr4 and Trf4-Air2. Proceedings of the National Academy of Sciences of the United States of America 2 39752526
2023 Conserved Residues at the Mtr4 C-Terminus Coordinate Helicase Activity and Exosome Interactions. Biochemistry 2 38085597
2025 The nuclear exosome co-factor MTR4 shapes the transcriptome for meiotic initiation. Nature communications 1 40097464
2025 Nucleolar Proteomics Revealed the Regulation of RNA Exosome Localization by MTR4. Molecular & cellular proteomics : MCP 1 40651665
2024 The MTR4/hnRNPK complex surveils aberrant polyadenylated RNAs with multiple exons. Nature communications 1 39419981
2011 A zebrafish SKIV2L2-enhancer trap line provides a useful tool for the study of peripheral sensory circuit development. Gene expression patterns : GEP 1 21742057
2025 N-Terminus of Cid14 Activates RNA Unwinding by Mtr4 in the Schizosaccharomyces pombe TRAMP Complex. Biochemistry 0 40519184
2025 MTR4 methylation-dependent degradation activates mTORC1 signaling to promote glioma cell survival under methionine starvation. Amino acids 0 41428109
2024 TRAMP assembly alters the conformation and RNA binding of Mtr4 and Trf4-Air2. bioRxiv : the preprint server for biology 0 39211223

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