Affinage

XRN2

5'-3' exoribonuclease 2 · UniProt Q9H0D6

Length
950 aa
Mass
108.6 kDa
Annotated
2026-04-28
58 papers in source corpus 37 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

XRN2 is a nuclear 5′→3′ exoribonuclease that serves as the central effector of RNA polymerase II transcriptional termination and a key mediator of nuclear RNA surveillance. In the torpedo mechanism of termination, XRN2 loads onto 5′-PO₄ ends generated by CPSF73 cleavage at poly(A) sites and processively degrades the downstream nascent RNA to dislodge RNAPII from DNA, a process gated by senataxin-mediated R-loop resolution, enhanced by Cdk9 phosphorylation at Thr439, and facilitated by cofactors including p54nrb/PSF and XTB-domain proteins (PAXT-1/NKRF/CDKN2AIP) that stabilize and localize the enzyme (PMID:15565158, PMID:21700224, PMID:26728557, PMID:24462208, PMID:29432121). Beyond poly(A)-dependent termination, XRN2 mediates promoter-proximal premature termination coupled to decapping, processes pre-rRNA (5.8S/28S maturation) through nucleolar targeting by NKRF/DHX15, degrades m7G-hypomodified tRNAs and tRNA trailer fragments, and cotranscriptionally eliminates aberrantly spliced or processed pre-mRNAs (PMID:22483619, PMID:21036871, PMID:28115624, PMID:22522706, PMID:37146074). XRN2 also resolves transcription-associated R-loops to suppress DNA double-strand breaks and genomic instability, with its recruitment to R-loop-prone loci regulated by RNF8-mediated ubiquitylation, and its loss causing synthetic lethality with PARP inhibition (PMID:27437695, PMID:37697435, PMID:32859985).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2004 High

    The central question of how RNAPII terminates transcription beyond poly(A) sites was answered by showing that XRN2 degrades the downstream RNA cleavage product to physically displace the polymerase — establishing the torpedo model.

    Evidence siRNA knockdown, transcriptional run-on, ChIP, and in vitro CoTC cleavage assays in human cells

    PMID:15565158

    Open questions at the time
    • Identity of the endonuclease generating the 5′ entry site was not yet resolved
    • Generality of the torpedo mechanism across genes was untested
    • Whether additional cofactors were required for XRN2 recruitment was unknown
  2. 2007 High

    The question of how XRN2 reaches the 3′ cleavage site was addressed by identifying p54nrb/PSF as a physical partner that recruits XRN2 to 3′-processing complexes.

    Evidence Reciprocal Co-IP, in vitro 3′-processing assays, ChIP, and siRNA knockdown with readthrough phenotype

    PMID:17639083

    Open questions at the time
    • Whether p54nrb/PSF acts on all genes or a subset was unclear
    • Direct vs. bridged interaction not fully resolved
  3. 2010 High

    Beyond mRNA termination, XRN2 was shown to have a distinct function in pre-rRNA processing, mediating 5′-end maturation of 5.8S and 28S rRNA and degrading aberrant pre-rRNA species in mammalian cells.

    Evidence siRNA knockdown in mouse cells with Northern blotting and pulse-chase analysis of pre-rRNA intermediates

    PMID:21036871

    Open questions at the time
    • How XRN2 is targeted to nucleolar pre-ribosomal complexes was unknown
    • Relationship between rRNA processing and mRNA termination functions was unclear
  4. 2011 High

    The puzzle of how XRN2 accesses nascent RNA at R-loop-forming termination zones was resolved by demonstrating that senataxin helicase must first resolve RNA:DNA hybrids at G-rich pause sites to expose the 3′ cleavage product.

    Evidence RNase H treatment, R-loop immunoprecipitation, siRNA knockdown of senataxin and XRN2, ChIP

    PMID:21700224

    Open questions at the time
    • Whether other helicases contribute to R-loop resolution for torpedo termination was untested
    • Structural basis of senataxin–XRN2 cooperation was unknown
  5. 2012 High

    Three contemporaneous studies expanded XRN2's role beyond 3′-end termination: it participates in promoter-proximal premature termination coupled to decapping (with Dcp1a/Dcp2/Edc3), Microprocessor-directed termination at HIV-1, and cotranscriptional quality control of aberrantly spliced pre-mRNAs.

    Evidence Co-IP, ChIP-seq, siRNA knockdown with pol II redistribution (promoter-proximal); ChIP-seq and KD at HIV-1 locus; Northern/RT-PCR with splicing inhibition

    PMID:22483619 PMID:22522706 PMID:22980978

    Open questions at the time
    • Relative contribution of 5′→3′ vs. 3′→5′ degradation in pre-mRNA surveillance was not quantified
    • Whether promoter-proximal termination uses the same torpedo mechanism as 3′-end termination was unclear
  6. 2014 High

    Discovery of the conserved XTB domain (XTBD/DUF3469) in PAXT-1 and mammalian homologs CDKN2AIP and NKRF revealed a dedicated protein family that stabilizes and localizes XRN2, answering the question of how XRN2 protein levels and compartmentalization are regulated.

    Evidence TALEN-mediated genome editing in C. elegans, Co-IP, in vivo rescue, miRNA turnover assays; cross-species binding validation

    PMID:24462208

    Open questions at the time
    • Structural basis of the XTBD–XRN2 interaction was not yet determined
    • Functional specialization among different XTBD-containing proteins in mammals was unresolved
  7. 2015 High

    Using a dominant-negative catalytically dead XRN2 mutant combined with pol II elongation rate mutants, the torpedo mechanism was demonstrated to operate genome-wide at most poly(A) sites via kinetic competition between XRN2 degradation speed and RNAPII elongation rate.

    Evidence Catalytically inactive XRN2 expression, pol II rate mutants, GRO-seq and ChIP-seq

    PMID:26474067

    Open questions at the time
    • Whether kinetic competition parameters differ across gene classes was not resolved
    • Post-translational regulation of XRN2 processivity in vivo was unknown
  8. 2016 High

    The structural basis of XRN2 stabilization was revealed: crystal/NMR structures showed that a single XTBD residue bridges two XRN2 domains, and Cdk9-mediated phosphorylation at Thr439 was identified as a direct activating modification that enhances XRN2 activity and chromatin recruitment.

    Evidence Crystal/NMR structures with mutagenesis and in vivo rescue (XTBD); chemical genetic kinase screen, in vitro kinase/activity assays, phosphomimetic mutants, ChIP, GRO-seq (Cdk9)

    PMID:26728557 PMID:26779609

    Open questions at the time
    • Whether additional kinases or phosphorylation sites regulate XRN2 was unknown
    • How phosphorylation alters XRN2 structure/dynamics was not resolved
  9. 2016 High

    XRN2 loss was shown to cause R-loop accumulation, DNA double-strand breaks, and genomic instability at transcriptional pause sites, establishing XRN2 as a genome stability factor beyond its role in transcription termination.

    Evidence siRNA knockdown, DRIP, γH2AX foci, comet assay, immunofluorescence with 53BP1 co-localization

    PMID:27437695

    Open questions at the time
    • Whether XRN2's genome stability role is entirely through R-loop resolution or involves additional mechanisms was unclear
    • Direct enzymatic activity on R-loop RNA substrates was not demonstrated in vitro
  10. 2017 High

    The question of how XRN2 reaches nucleolar pre-ribosomal substrates was answered by identifying a pre-ribosomal subcomplex of NKRF, DHX15 helicase, and XRN2, with NKRF being required for nucleolar XRN2 recruitment and early pre-rRNA cleavage.

    Evidence CRAC, reciprocal Co-IP, siRNA knockdown, Northern blotting of pre-rRNA intermediates

    PMID:28115624

    Open questions at the time
    • Whether DHX15 helicase activity is required for XRN2 substrate access in the nucleolus was untested
    • How CARF and NKRF coordinate to partition XRN2 between nucleolus and nucleoplasm was unclear
  11. 2018 High

    Rapid conditional depletion confirmed that XRN2 is required genome-wide for cotranscriptional degradation of 3′-flanking RNA and termination at protein-coding genes, dependent on prior CPSF73 cleavage, but dispensable for histone and snRNA gene termination.

    Evidence Auxin-inducible degron depletion, mNET-seq, catalytically inactive CPSF73 rescue

    PMID:29432121

    Open questions at the time
    • Mechanism of termination at histone/snRNA genes that does not require XRN2 was not defined
    • Whether other 5′→3′ exonucleases partially compensate was not addressed
  12. 2019 High

    Rapid depletion studies clarified that XRN2 has little role in degrading canonical exosome substrates (eRNAs, PROMPTs) but instead mediates distinct early termination pathways at protein-coding gene promoters, delineating functional boundaries between 5′→3′ and 3′→5′ nuclear RNA decay.

    Evidence Auxin-inducible degron depletion, RNA-seq, comparison with DIS3/EXOSC10 depletion

    PMID:30840897

    Open questions at the time
    • Molecular basis for substrate selectivity between XRN2 and the exosome was not resolved
  13. 2022 High

    NMR dynamics studies revealed that XRN2's catalytic center is conformationally dynamic in the apo state and that substrate/Mg²⁺ binding shifts the equilibrium toward the active conformation — providing a structural explanation for processivity regulation.

    Evidence Fluorine and methyl-TROSY NMR, site-directed mutagenesis, in vitro RNA degradation assays

    PMID:36008487

    Open questions at the time
    • Whether cofactor binding (XTBD proteins, phosphorylation) affects these dynamics was not tested
    • No structural snapshots of XRN2 engaged with full-length RNA substrates
  14. 2022 High

    Genome-wide substrate mapping with an exonuclease-dead mutant pinpointed XRN2 loading sites to 2–20 bases downstream of CPSF73 cleavage at poly(A) sites, histone 3′ ends, and RNase Z-generated tRNA 3′ ends, and confirmed XRN2 requirement for both poly(A) and promoter-proximal termination.

    Evidence Active-site mutant (D235A) substrate trapping, eNET-seq, ChIP-seq, 5′-PO₄ end mapping

    PMID:36396340

    Open questions at the time
    • How XRN2 is loaded onto the 5′-PO₄ end in the context of the elongation complex was not structurally resolved
    • Kinetics of loading in vivo were not measured
  15. 2023 High

    RNF8-mediated ubiquitylation of XRN2 was identified as a mechanism for targeting XRN2 to R-loop-prone loci, with RNF8 deficiency in BRCA1-mutant cells causing R-loop accumulation, transcription-replication collisions, and synthetic lethality.

    Evidence Ubiquitylation assays, Co-IP, DRIP-seq, ChIP-seq, siRNA knockdown, mouse mammary tumorigenesis model

    PMID:37697435

    Open questions at the time
    • Specific ubiquitylation sites on XRN2 and how they alter its localization or activity were not fully mapped
    • Whether this pathway operates in non-cancer contexts was unclear
  16. 2023 Medium

    XRN2 was established as the enzyme that degrades tRNA trailer fragments (tRF-1s) in the nucleus, preventing their aberrant loading into Ago2/RISC and thus acting as a gatekeeper of small RNA pathway selectivity.

    Evidence siRNA knockdown, small RNA sequencing, Ago2 immunoprecipitation, tRF-1 stability assays

    PMID:37146074

    Open questions at the time
    • Whether XRN2 acts on all tRF-1 species or a subset was not fully resolved
    • In vitro reconstitution of XRN2 activity on tRNA trailers was not shown
  17. 2024 Medium

    Cryo-EM and crystallographic structures of the yeast/fungal Rat1–Rai1–Rtt103 torpedo complex revealed a conserved protein core but species-specific variation in interaction interfaces, framing how cofactor organization around XRN2/Rat1 has diverged.

    Evidence Cryo-EM and X-ray crystallography of S. cerevisiae and C. thermophilum complexes

    PMID:39657659

    Open questions at the time
    • No structure of the human XRN2 torpedo complex exists
    • Functional validation of species-specific interface residues was limited

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how XRN2 is handed off from the CPSF73 cleavage site to the nascent RNA in the context of the elongating RNAPII complex, how its multiple post-translational modifications (phosphorylation, ubiquitylation) are coordinated, and how substrate selectivity between XRN2 and the nuclear exosome is determined at the molecular level.
  • No structure of human XRN2 engaged with an RNAPII elongation complex
  • Integration of multiple PTM signals on XRN2 not systematically studied
  • Molecular determinants of substrate triage between XRN2 and the exosome are undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 10 GO:0016787 hydrolase activity 5 GO:0003723 RNA binding 3
Localization
GO:0005634 nucleus 8 GO:0005730 nucleolus 4 GO:0005694 chromosome 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-74160 Gene expression (Transcription) 7 R-HSA-8953854 Metabolism of RNA 5 R-HSA-392499 Metabolism of proteins 3 R-HSA-73894 DNA Repair 3 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
CDK9CPSF73DHX15NKRFNONORNF8SETXSFPQ
Complex memberships
NKRF–DHX15–XRN2 pre-ribosomal subcomplexXTBD–XRN2 stabilization complex (PAXT-1/CDKN2AIP/NKRF)

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Human XRN2 (5'→3' exonuclease) degrades the downstream RNA cleavage product generated by co-transcriptional cleavage (CoTC) autocatalytic activity at the beta-globin gene poly(A) signal, thereby inducing RNA polymerase II dissociation from the DNA template — the 'torpedo' model of transcriptional termination. siRNA knockdown of XRN2, transcriptional run-on assays, and ChIP analysis in human cells; in vitro CoTC cleavage assays Nature High 15565158
2007 XRN2 physically associates with 3'-processing factors and the multifunctional protein p54nrb/PSF; p54nrb/PSF is required for recruitment of XRN2 to the 3' end of transcribed genes and for degradation of the downstream 3'-cleaved RNA to promote transcription termination. Co-immunoprecipitation, in vitro 3'-processing/cleavage assays, ChIP, siRNA knockdown with transcriptional readthrough phenotype Genes & development High 17639083
2011 Senataxin helicase resolves R-loop structures (RNA/DNA hybrids) that form over G-rich pause sites downstream of poly(A) signals, thereby allowing access of XRN2 to the 3' cleavage product; this R-loop resolution is a prerequisite for XRN2-mediated torpedo termination. RNase H treatment, R-loop immunoprecipitation, siRNA knockdown of senataxin and XRN2, transcription termination assays, ChIP Molecular cell High 21700224
2012 Decapping proteins Edc3, Dcp1a, and Dcp2 co-immunoprecipitate with XRN2 and the termination factor TTF2; knockdown of decapping factors or XRN2 and TTF2 shifts RNA polymerase II away from the TSS, indicating coupled cotranscriptional decapping and premature termination by the torpedo mechanism near promoter-proximal pause sites. Co-immunoprecipitation, ChIP-seq, siRNA knockdown with pol II redistribution phenotype Molecular cell High 22483619
2012 Microprocessor (Drosha/DGCR8) orchestrates recruitment of Setx and XRN2, and the 3'-5' exoribonuclease Rrp6, to initiate RNAPII pausing and premature termination at the HIV-1 promoter through cleavage of the stem-loop RNA TAR, revealing cooperative exoribonuclease activity in transcription regulation. ChIP-seq, siRNA knockdown, Co-IP, genome-wide analysis of transcription elongation Cell High 22980978
2012 XRN2 associates with and co-transcriptionally degrades nascent pre-mRNA transcripts when splicing or 3'-end processing is inhibited, establishing a co-transcriptional pre-mRNA quality control function for XRN2. siRNA knockdown of XRN2, RT-PCR/Northern blotting for aberrant transcript accumulation, Spliceostatin A treatment, ChIP The EMBO journal High 22522706
2014 Hepatitis C virus subverts the liver-specific microRNA miR-122 to protect the viral RNA 5' end from degradation by XRN2; XRN2 depletion increases HCV RNA abundance by affecting viral RNA stability (not replication or translation), and XRN2 depletion eliminates the miR-122 requirement for HCV RNA stability. siRNA knockdown of XRN2, HCV RNA stability assays, luciferase reporter assays, miR-122 sequestration experiments Cell host & microbe High 25121753
2015 Using a dominant-negative catalytically inactive XRN2 mutant, XRN2 exonuclease activity was shown to be required for transcription termination genome-wide at most poly(A) sites, with kinetic competition between XRN2 and pol II elongation speed being integral to determining the zone of termination. Dominant-negative XRN2 mutant expression, pol II rate mutants, GRO-seq/ChIP-seq genome-wide analysis Molecular cell High 26474067
2016 Cdk9 (P-TEFb) phosphorylates XRN2 at Thr439, enhancing its enzymatic activity on synthetic substrates in vitro; phosphomimetic substitution at Thr439 promotes XRN2 chromatin localization, while non-phosphorylatable mutation or Cdk9 inhibition impairs XRN2 chromatin recruitment and increases transcriptional readthrough. Chemical genetic kinase screen, in vitro kinase assay, XRN2 activity assay on synthetic substrates, phosphomimetic/non-phosphorylatable mutants, ChIP, GRO-seq Genes & development High 26728557
2016 XRN2 loss leads to increased R-loops, DNA double-strand breaks at transcriptional pause sites, replication stress, and genomic instability; XRN2 undergoes DNA damage-inducible nuclear re-localization to 53BP1 and R-loop foci, revealing a role in R-loop resolution and DNA damage response. siRNA knockdown, immunofluorescence co-localization, comet assay, DNA-RNA immunoprecipitation (DRIP), γH2AX foci, flow cytometry PLoS genetics High 27437695
2018 Conditional depletion of XRN2 via gene editing causes a clear, general defect in cotranscriptional degradation of 3'-flanking RNA and transcriptional termination at protein-coding genes genome-wide, dependent on prior RNA cleavage by CPSF73; XRN2 plays no significant role in histone or snRNA gene termination. Auxin-inducible degron gene editing for rapid protein depletion, mNET-seq genome-wide nascent RNA sequencing, catalytically inactive CPSF73 rescue Genes & development High 29432121
2010 In mammalian cells, XRN2 mediates 5'-end maturation of 5.8S and 28S rRNA precursors and also degrades aberrant pre-rRNA species in a 5'→3' direction, a function previously attributed mainly to 3' exonucleases in yeast. siRNA knockdown in mouse cells, Northern blotting, pulse-chase analysis of pre-rRNA processing intermediates Nucleic acids research High 21036871
2017 The G-patch protein NKRF forms a pre-ribosomal subcomplex with DHX15 helicase and XRN2; NKRF is required for recruitment of XRN2 to nucleolar pre-ribosomal complexes, and depletion of NKRF or XRN2 impairs an early pre-rRNA cleavage step (A') and causes accumulation of excised spacer fragments. Co-immunoprecipitation, UV crosslinking and analysis of cDNA (CRAC), siRNA knockdown, Northern blotting, pre-rRNA processing assays Nucleic acids research High 28115624
2014 The C. elegans protein PAXT-1 (R05D11.6) forms a complex with XRN2 and stabilizes it; the XRN2-binding domain (XTBD/DUF3469) within PAXT-1 is sufficient to restore viability to paxt-1 mutants and elevate XRN2 levels; mammalian homologs CDKN2AIP/CARF and NKRF interact with XRN2 via the same conserved XTBD domain. TALEN-mediated genome editing, co-immunoprecipitation, in vivo rescue assays, miRNA turnover assays Molecular cell High 24462208
2016 Crystal/solution structure characterization of the XTBD–XRN2 complex reveals that a single critical XTBD residue mediates stable interconnection of two XRN2 domains; vertebrate XTBD-containing proteins (CDKN2AIPNL) can bind XRN2 in vitro and substitute for PAXT-1 in vivo, demonstrating conservation of the XTBD–XRN2 interaction mode. Structural biology (crystal/NMR), mutagenesis, in vitro binding assays, in vivo rescue in C. elegans Nature structural & molecular biology High 26779609
2022 NMR spectroscopy (fluorine and methyl-TROSY) reveals that Xrn2 is highly dynamic around its catalytic center in the apo state; substrate and Mg2+ shift the conformational equilibrium toward an active state, and a mutation attenuating these dynamics also reduces catalytic activity. Fluorine and methyl-TROSY NMR spectroscopy, in vitro RNA degradation assays, site-directed mutagenesis Nature chemical biology High 36008487
2022 Xrn2 is recruited to preinitiation complexes and loads onto nascent RNA 5'-PO4 ends approximately 2–20 bases downstream of CPSF73 cleavage at polyA sites and histone 3' ends; RNase Z cleavage at tRNA 3' ends also generates Xrn2 substrates; exonuclease-dead Xrn2(D235A) causes defects in both poly(A) site termination and promoter-proximal premature termination genome-wide. Xrn2 substrate mapping with active-site mutant (D235A) stabilization, eNET-seq, ChIP-seq, nascent RNA 5'-PO4 end mapping Genes & development High 36396340
2019 Rapid conditional depletion of XRN2 (using the auxin-inducible degron system) reveals that XRN2 has little activity on exosome substrates (enhancer RNAs, PROMPTs, PCPA products) but uncovers distinct mechanisms for early termination from protein-coding gene promoters. Auxin-inducible degron rapid depletion, RNA-seq, comparison with DIS3 and EXOSC10 depletion phenotypes Cell reports High 30840897
2023 RNF8 E3 ubiquitin ligase ubiquitylates XRN2 and promotes its recruitment to R-loop-prone genomic loci; RNF8 deficiency in BRCA1-mutant cells decreases XRN2 occupancy at these sites, causing R-loop accumulation, transcription-replication collisions, and synthetic lethality. Co-immunoprecipitation, ubiquitylation assays, DRIP-seq, ChIP-seq, siRNA knockdown, genetic mouse mammary tumorigenesis model Nucleic acids research High 37697435
2015 In fission yeast, the Xrn2 ortholog Dhp1/Rat1 cooperates with RNA elimination factors to promote premature termination and facultative heterochromatin formation at meiotic genes; Dhp1 interacts with the Clr4/Suv39h methyltransferase complex and directly nucleates heterochromatin, linking transcription termination machinery to gene silencing. Genetic epistasis, Co-immunoprecipitation, ChIP-seq, reporter silencing assays in S. pombe Proceedings of the National Academy of Sciences of the United States of America High 26631744
2015 CARF (collaborator of ARF/CDKN2AIP) associates with XRN2 and sequesters it in the nucleoplasm; CARF overexpression suppresses XRN2 nucleolar localization and pre-rRNA processing, while CARF knockdown increases XRN2 nucleolar fraction — establishing CARF as a spatial regulator of XRN2 in ribosome biogenesis. Co-immunoprecipitation, cell fractionation, immunocytochemistry, overexpression/knockdown with pre-rRNA accumulation readout Nucleic acids research Medium 26531822
2020 Full-length NKRF contains an N-terminal XTBD that tethers XRN2 in the nucleolus by binding rRNA; this XTBD is essential for retention of XRN2 in the nucleolus and for early pre-rRNA processing. Identification of alternative upstream AUG, domain deletion analysis, Co-immunoprecipitation, RNA immunoprecipitation, subcellular localization The Biochemical journal Medium 32011671
2013 hnRNPK knockdown reduces XRN2 recruitment to the EGR1 gene and its downstream poly(A) region, leading to increased readthrough transcription; hnRNPK and XRN2 are found in the same nuclear complex by co-immunoprecipitation and mass spectrometry. ChIP-seq, siRNA knockdown, co-immunoprecipitation, mass spectrometry The Journal of biological chemistry Medium 23857582
2016 The transcription factor Nkx2-5 binds downstream regions of cardiac genes and controls XRN2 occupancy at these loci; Nkx2-5 deficiency reduces XRN2 binding and increases RNAPII occupancy, leading to increased expression of transcripts with long 3' UTRs; genetic interaction between Nkx2-5(+/-) and Xrn2(+/-) produces ventricular septal defects, demonstrating functional cooperation in alternative polyadenylation during heart development. ChIP-seq, siRNA knockdown, genetic compound heterozygote mouse model, RNA-seq eLife Medium 27331609
2020 XRN2 depletion causes R-loop gains at transcription termination sites of highly transcribed genes genome-wide; DDX5, XRN2, and PRMT5 share R-loop gain loci at termination sites, consistent with coordinated roles in RNAPII termination, while DDX5 has unique R-loop gain peaks near TSS independent of XRN2. DRIP-seq genome-wide R-loop mapping in XRN2-depleted U2OS cells, siRNA knockdown Life science alliance Medium 32747416
2022 XRN2 promotes recruitment of the RNA-binding protein Sam68 to target transcripts; the Sam68/XRN2 complex competes with CPSF for binding to distal polyadenylation signals, thereby promoting usage of proximal polyadenylation signals and 3' UTR shortening to drive G1/S cell cycle progression in prostate cancer. Genome-wide transcriptome profiling (APA analysis), RNA immunoprecipitation, co-immunoprecipitation, siRNA knockdown, luciferase assays Nature structural & molecular biology Medium 36344846
2020 XRN2 associates with DNA repair/replication proteins (Ku70-Ku80, DNA-PKcs, PARP1, MCM2-7, PCNA, RPA1) and RNA metabolism factors by tandem affinity purification-mass spectrometry; XRN2-deficient cells show synthetic lethality with PARP1 inhibition and enhanced PARP1 activity. Tandem affinity purification-mass spectrometry (TAP-MS), siRNA knockdown, cell viability assays, PARP1 activity assay Scientific reports Medium 32859985
2020 XRN2-mediated RNA:DNA hybrid resolution is required for Ku70 binding to DNA ends, enabling non-homologous end-joining (NHEJ) repair; XRN2 loss also impairs homologous recombination repair through a distinct mechanism involving unregulated transcription at DSB sites. siRNA knockdown, Ku70 ChIP at DSB sites, RNaseH1 overexpression rescue, HR and NHEJ reporter assays, DRIP Cancers Medium 32645903
2022 CAPRIN1 associates with XRN2 in small nuclear RNA granules during early ESC differentiation; CAPRIN1 promotes XRN2-dependent degradation of thousands of RNA transcripts, and CAPRIN1 nuclear localization and colocalization with XRN2 are CAPRIN1-dependent. RIP-seq, SLAM-seq, co-immunoprecipitation, immunofluorescence, CAPRIN1 knockout ESCs Developmental cell Medium 36495875
2011 NPGPx covalently binds to XRN2 upon non-targeting siRNA stress and facilitates XRN2-mediated degradation of accumulated non-targeting siRNAs, revealing a stress-response role for XRN2 in siRNA clearance. Co-immunoprecipitation, siRNA depletion, cell growth/apoptosis assays, covalent crosslinking analysis Nucleic acids research Low 21908404
2015 XRN2 is the primary nuclear 5'→3' exoribonuclease responsible for degrading the 3' fragments of target pre-mRNA generated after RNase H1-mediated antisense oligonucleotide (ASO) cleavage in the nucleus, while cytoplasmic XRN1 handles mature mRNA 3' fragments. siRNA depletion of XRN1 and XRN2, measurement of 3' cleavage fragment levels by Northern/RT-PCR in vitro and in cells Biochemical and biophysical research communications Low 26159921
2023 XRN2 regulates the stability of the long non-coding telomeric RNA TERRA; depletion of XRN2 in ALT-positive cancer cells increases TERRA R-loops and exacerbates ALT activity. siRNA knockdown, RNA stability assays, R-loop immunofluorescence (S9.6), ALT activity assays (FISH) FEBS letters Low 37191774
2023 XRN2 degrades tRNA trailers (tRF-1s) in the nucleus, preventing their aberrant accumulation in RISC/Argonaute2; XRN2 depletion stabilizes tRF-1s and increases their Ago2 loading, demonstrating a role in RISC selectivity. siRNA knockdown of XRN2, small RNA sequencing, Ago2 immunoprecipitation, tRF-1 stability assays PLoS genetics Medium 37146074
2024 Structural analysis by cryo-EM and crystallography of the Xrn2/Rat1–Rai1–Rtt103 torpedo termination complex from S. cerevisiae and C. thermophilum reveals a conserved protein core but significant variability in interaction interfaces between species, with Rtt103 using different structural elements to bind Rai1 in each organism. Cryo-EM, X-ray crystallography, structural comparison across species Structure Medium 39657659
2025 XRN2 knockdown restores tRNA levels diminished by METTL1 depletion (m7G hypomodification) in human cells, demonstrating that XRN2 mediates accelerated decay of m7G-hypomodified tRNAs under normal (non-heat stress) physiological conditions as part of a constitutive rapid tRNA decay pathway. siRNA knockdown, conditional protein knockdown (auxin-inducible degron), time-resolved tRNA level measurements, tRNA decay kinetics, Drosophila genetic rescue bioRxivpreprint Medium
2025 HELQ helicase functionally interacts with XRN2 for R-loop resolution; HELQ unwinds R-loops in an ATPase/helicase-dependent manner and coordinates with XRN2 for RNA digestion, as demonstrated in vitro and in cells. Co-immunoprecipitation, in vitro R-loop unwinding assays, cell-based R-loop quantification, catalytic mutant analysis Open biology Medium 39965657
2017 XRN2 accelerates pre-miR-10a maturation by binding to pre-miR-10a in a DICER-independent manner, promoting EMT and metastasis in lung cancer cells. RNA immunoprecipitation, overexpression/knockdown, in vitro and in vivo metastasis assays Oncogene Low 28319071
2025 The lncRNA GDIL re-localizes XRN2 from the nucleus to the cytoplasm, where it scaffolds XRN2 to identify and degrade CHAC1 mRNA, thereby inhibiting glutathione degradation and promoting platinum resistance in colorectal cancer. RNA immunoprecipitation, subcellular fractionation, mRNA stability assays, GDIL knockdown/overexpression Cell death & disease Low 39893168

Source papers

Stage 0 corpus · 58 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Molecular cell 671 21700224
2004 Human 5' --> 3' exonuclease Xrn2 promotes transcription termination at co-transcriptional cleavage sites. Nature 388 15565158
2007 Arabidopsis FIERY1, XRN2, and XRN3 are endogenous RNA silencing suppressors. The Plant cell 233 17993620
2012 mRNA decapping factors and the exonuclease Xrn2 function in widespread premature termination of RNA polymerase II transcription. Molecular cell 175 22483619
2015 Effects of Transcription Elongation Rate and Xrn2 Exonuclease Activity on RNA Polymerase II Termination Suggest Widespread Kinetic Competition. Molecular cell 174 26474067
2007 The multifunctional protein p54nrb/PSF recruits the exonuclease XRN2 to facilitate pre-mRNA 3' processing and transcription termination. Genes & development 151 17639083
2012 Microprocessor, Setx, Xrn2, and Rrp6 co-operate to induce premature termination of transcription by RNAPII. Cell 149 22980978
2016 P-TEFb regulation of transcription termination factor Xrn2 revealed by a chemical genetic screen for Cdk9 substrates. Genes & development 119 26728557
2012 A Tetrahymena Piwi bound to mature tRNA 3' fragments activates the exonuclease Xrn2 for RNA processing in the nucleus. Molecular cell 112 23084833
2014 Hepatitis C virus subverts liver-specific miR-122 to protect the viral genome from exoribonuclease Xrn2. Cell host & microbe 103 25121753
2018 Xrn2 accelerates termination by RNA polymerase II, which is underpinned by CPSF73 activity. Genes & development 102 29432121
2016 XRN2 Links Transcription Termination to DNA Damage and Replication Stress. PLoS genetics 97 27437695
2010 Arabidopsis thaliana XRN2 is required for primary cleavage in the pre-ribosomal RNA. Nucleic acids research 87 20338880
2010 5'-end surveillance by Xrn2 acts as a shared mechanism for mammalian pre-rRNA maturation and decay. Nucleic acids research 78 21036871
2012 Co-transcriptional degradation of aberrant pre-mRNA by Xrn2. The EMBO journal 77 22522706
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
2017 The G-patch protein NF-κB-repressing factor mediates the recruitment of the exonuclease XRN2 and activation of the RNA helicase DHX15 in human ribosome biogenesis. Nucleic acids research 59 28115624
2015 Conserved factor Dhp1/Rat1/Xrn2 triggers premature transcription termination and nucleates heterochromatin to promote gene silencing. Proceedings of the National Academy of Sciences of the United States of America 58 26631744
2015 Dissecting the roles of the 5' exoribonucleases Xrn1 and Xrn2 in restricting hepatitis C virus replication. Journal of virology 57 25673723
2020 Genome-wide R-loop analysis defines unique roles for DDX5, XRN2, and PRMT5 in DNA/RNA hybrid resolution. Life science alliance 55 32747416
2013 The multifunctional RNase XRN2. Biochemical Society transactions 40 23863139
2016 A Novel Epigenetic Silencing Pathway Involving the Highly Conserved 5'-3' Exoribonuclease Dhp1/Rat1/Xrn2 in Schizosaccharomyces pombe. PLoS genetics 36 26889830
2022 Xrn2 substrate mapping identifies torpedo loading sites and extensive premature termination of RNA pol II transcription. Genes & development 31 36396340
2013 Heterogeneous nuclear ribonucleoprotein (HnRNP) K genome-wide binding survey reveals its role in regulating 3'-end RNA processing and transcription termination at the early growth response 1 (EGR1) gene through XRN2 exonuclease. The Journal of biological chemistry 30 23857582
2014 Engineering of a conditional allele reveals multiple roles of XRN2 in Caenorhabditis elegans development and substrate specificity in microRNA turnover. Nucleic acids research 27 24445807
2014 PAXT-1 promotes XRN2 activity by stabilizing it through a conserved domain. Molecular cell 26 24462208
2017 XRN2 promotes EMT and metastasis through regulating maturation of miR-10a. Oncogene 25 28319071
2009 Genetic variants cis-regulating Xrn2 expression contribute to the risk of spontaneous lung tumor. Oncogene 23 19915612
2011 Label-free quantitative proteomics reveals regulation of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) and 5'-3'-exoribonuclease 2 (XRN2) during respiratory syncytial virus infection. Virology journal 22 21933386
2015 Collaborator of alternative reading frame protein (CARF) regulates early processing of pre-ribosomal RNA by retaining XRN2 (5'-3' exoribonuclease) in the nucleoplasm. Nucleic acids research 21 26531822
2011 Non-targeting siRNA induces NPGPx expression to cooperate with exoribonuclease XRN2 for releasing the stress. Nucleic acids research 21 21908404
2023 RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells. Nucleic acids research 20 37697435
2020 LSM2-8 and XRN-2 contribute to the silencing of H3K27me3-marked genes through targeted RNA decay. Nature cell biology 19 32251399
2016 Regulation of alternative polyadenylation by Nkx2-5 and Xrn2 during mouse heart development. eLife 19 27331609
2022 Observation of conformational changes that underlie the catalytic cycle of Xrn2. Nature chemical biology 18 36008487
2022 The transcriptional terminator XRN2 and the RNA-binding protein Sam68 link alternative polyadenylation to cell cycle progression in prostate cancer. Nature structural & molecular biology 17 36344846
2018 An end in sight? Xrn2 and transcriptional termination by RNA polymerase II. Transcription 16 30035655
2022 RNA degradation eliminates developmental transcripts during murine embryonic stem cell differentiation via CAPRIN1-XRN2. Developmental cell 15 36495875
2020 XRN2 Links RNA:DNA Hybrid Resolution to Double Strand Break Repair Pathway Choice. Cancers 15 32645903
2016 Structural basis and function of XRN2 binding by XTB domains. Nature structural & molecular biology 15 26779609
2020 XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition. Scientific reports 13 32859985
2016 XRN2 Autoregulation and Control of Polycistronic Gene Expresssion in Caenorhabditis elegans. PLoS genetics 13 27631780
1999 Cloning and mapping of the XRN2 gene to human chromosome 20p11.1-p11.2. Genomics 12 10409438
2025 Long noncoding RNA GDIL acts as a scaffold for CHAC1 and XRN2 to promote platinum resistance of colorectal cancer through inhibition of glutathione degradation. Cell death & disease 9 39893168
2015 XRN2 is required for the degradation of target RNAs by RNase H1-dependent antisense oligonucleotides. Biochemical and biophysical research communications 9 26159921
2023 The exoribonuclease XRN2 mediates degradation of the long non-coding telomeric RNA TERRA. FEBS letters 8 37191774
2020 Full-length NF-κB repressing factor contains an XRN2 binding domain. The Biochemical journal 7 32011671
2025 Nsclc-derived exosomal hsa_circ_0003026 promotes tumor growth through macrophage M2 polarization via hsa-miR-1183/XRN2 axis. Gene 6 40345505
2022 XRN2 Is Required for Cell Motility and Invasion in Glioblastomas. Cells 6 35563787
2023 XRN2 suppresses aberrant entry of tRNA trailers into argonaute in humans and Arabidopsis. PLoS genetics 5 37146074
2012 Rat1 and Xrn2: The Diverse Functions of the Nuclear Rat1/Xrn2 Exonuclease. The Enzymes 4 27166444
2012 An argonaute protein directs nuclear Xrn2 function. Molecular cell 3 23200120
2005 A novel splice variant of human XRN2 gene is mainly expressed in blood leukocyte. DNA sequence : the journal of DNA sequencing and mapping 3 16147866
2025 The human HELQ helicase and XRN2 exoribonuclease cooperate in R-loop resolution. Open biology 2 39965657
2024 Molecular Basis of XRN2-Deficient Cancer Cell Sensitivity to Poly(ADP-ribose) Polymerase Inhibition. Cancers 2 38339346
2021 Nuclear RNA Regulation by XRN2 and XTBD Family Proteins. Cell structure and function 2 34483148
2024 Assembly of the Xrn2/Rat1-Rai1-Rtt103 termination complexes in mesophilic and thermophilic organisms. Structure (London, England : 1993) 1 39657659
2023 A germline-targeted genetic screen for xrn-2 suppressors identifies a novel gene C34C12.2 in Caenorhabditis elegans. Genetics and molecular biology 0 37216322