Affinage

XRN2

5'-3' exoribonuclease 2 · UniProt Q9H0D6

Length
950 aa
Mass
108.6 kDa
Annotated
2026-06-11
56 papers in source corpus 39 papers cited in narrative 39 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

XRN2 is a nuclear 5'→3' exoribonuclease that enforces RNA polymerase II transcription termination genome-wide through the 'torpedo' mechanism: it loads onto the 5'-phosphate RNA end generated by CPSF73 cleavage at poly(A) sites and degrades the downstream nascent transcript to chase down and evict elongating Pol II (PMID:15565158, PMID:29432121, PMID:36396340). Mapping of XRN2 loading sites with a catalytically inactive mutant places handoff a few bases downstream of CPSF73 cleavage at poly(A) and histone 3' ends, and an analogous handoff occurs at tRNA 3' ends after RNase Z cleavage (PMID:36396340); XRN2 also degrades sense and antisense transcripts near the TSS to effect widespread promoter-proximal premature termination (PMID:36396340, PMID:22483619). The position of termination is set by kinetic competition between XRN2 exonuclease progression and Pol II elongation rate (PMID:26474067), and access to the cleaved product requires resolution of R-loops over G-rich pause sites by senataxin (PMID:21700224). XRN2 catalytic activity and chromatin loading are enhanced by CDK9/P-TEFb phosphorylation at Thr439 (PMID:26728557), its recruitment to gene 3' ends is mediated by interacting factors including p54nrb/PSF and hnRNPK (PMID:17639083, PMID:23857582), and conformational dynamics around its catalytic center are intrinsic to its degradation activity (PMID:36008487). Beyond termination, XRN2 carries out pre-rRNA maturation—generating 5' ends of 5.8S and 28S rRNA and executing an early A' cleavage step within an NKRF/DHX15 pre-ribosomal subcomplex (PMID:21036871, PMID:28115624). XRN2 protein stability and nucleoplasm/nucleolus partitioning are controlled by XTBD-domain proteins (PAXT-1, NKRF, CARF/CDKN2AIP), which dock onto and bridge two XRN2 domains (PMID:24462208, PMID:26779609, PMID:26531822, PMID:32011671). XRN2 additionally degrades aberrantly processed nascent pre-mRNAs co-transcriptionally (PMID:22522706), turns over specific miRNAs and hypomodified tRNAs [PMID:24445807, PMID:bio_10.1101_2025.11.05.686800], resolves R-loops to suppress genomic instability and enable DSB repair (PMID:27437695, PMID:32645903), and shapes alternative polyadenylation (PMID:36344846).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 2004 High

    Established the foundational 'torpedo' model—that a 5'→3' exonuclease degrades the downstream cleavage product to terminate Pol II transcription—answering how termination is mechanistically coupled to nascent RNA cleavage.

    Evidence siRNA knockdown of XRN2 with in vitro cleavage and nuclear run-on assays at the beta-globin gene

    PMID:15565158

    Open questions at the time
    • Demonstrated at a single gene rather than genome-wide
    • Did not define how XRN2 is recruited to the 3'-processing site
  2. 2007 High

    Identified how XRN2 is physically delivered to gene 3' ends, linking it to the cleavage/polyadenylation machinery via p54nrb/PSF.

    Evidence Co-IP, in vitro 3'-processing assays, ChIP and siRNA knockdown

    PMID:17639083

    Open questions at the time
    • XRN2 not required for the cleavage step itself
    • Recruitment mechanism beyond p54nrb/PSF unresolved
  3. 2010 High

    Extended XRN2 function beyond termination to ribosome biogenesis, showing it generates mature rRNA 5' ends and clears aberrant pre-rRNA.

    Evidence siRNA knockdown in mouse cells with Northern blotting and primer extension

    PMID:21036871

    Open questions at the time
    • Did not identify the nucleolar recruitment factors
    • Relationship to termination role not addressed
  4. 2011 High

    Defined a prerequisite for torpedo termination—senataxin must resolve R-loops behind paused Pol II so XRN2 can access the cleavage product.

    Evidence siRNA knockdown of senataxin and XRN2 with R-loop IF, nuclear run-on and ChIP

    PMID:21700224

    Open questions at the time
    • In vitro reconstitution of the senataxin–XRN2 handoff not shown
    • Generality across genes not established at this stage
  5. 2012 High

    Showed XRN2 termination is not restricted to gene 3' ends but limits bidirectional/promoter-proximal Pol II elongation through coupling to decapping and TTF2, and operates at the HIV-1 promoter downstream of Microprocessor cleavage.

    Evidence Co-IP, ChIP-seq and siRNA knockdown (decapping factors/TTF2; Drosha/DGCR8/Setx)

    PMID:22483619 PMID:22980978

    Open questions at the time
    • Direct vs indirect interactions with decapping factors not fully resolved
    • Substrate 5' end chemistry at promoters not mapped
  6. 2012 Medium

    Demonstrated XRN2 surveys nascent pre-mRNA and co-transcriptionally degrades transcripts that fail splicing or 3'-processing, broadening its role to RNA quality control.

    Evidence ChIP, RIP, siRNA knockdown, RT-PCR and Northern blotting with Spliceostatin A

    PMID:22522706

    Open questions at the time
    • Single lab
    • Recognition of aberrant transcripts mechanistically undefined
  7. 2014 High

    Identified the XTBD-domain protein family (PAXT-1 and human CARF/NKRF homologs) as conserved factors that bind XRN2 and stabilize the protein, defining a post-translational control layer.

    Evidence TALEN editing, Co-IP, complementation and survival assays in C. elegans

    PMID:24462208

    Open questions at the time
    • Structural basis of XTBD–XRN2 binding not yet resolved
    • Whether stabilization affects substrate selection unclear
  8. 2015 Medium

    Showed XRN2 turns over specific RNA substrates in trans—nuclear ASO/RNase H1-generated pre-mRNA 3' fragments—distinguishing its nuclear role from cytoplasmic XRN1.

    Evidence siRNA knockdown of XRN1/XRN2 with fragment Northern blotting and fractionation

    PMID:26159921

    Open questions at the time
    • Single method set
    • Endogenous physiological substrates of this activity not defined
  9. 2015 Medium

    Demonstrated that XTBD protein CARF controls XRN2 nucleoplasm/nucleolus partitioning and thereby tunes pre-rRNA processing.

    Evidence Co-IP, cell fractionation, immunocytochemistry and KD/overexpression with Northern blotting

    PMID:26531822

    Open questions at the time
    • Single lab
    • Signal triggering CARF-dependent relocalization unknown
  10. 2015 Medium

    Established a torpedo-independent function—nuclear stabilization of cytoplasmic HCV RNA antagonized by miR-122—indicating XRN2 substrate effects can be both degradative and protective in viral RNA metabolism.

    Evidence siRNA knockdown, overexpression, luciferase reporters and RNA stability assays

    PMID:25121753

    Open questions at the time
    • Mechanism of XRN2-mediated protection vs degradation unclear
    • Single lab
  11. 2015 High

    Proved the torpedo operates genome-wide and that termination position is governed by kinetic competition between XRN2 and Pol II elongation rate.

    Evidence Dominant-negative catalytic-dead XRN2 with Pol II rate mutants and PRO-seq/GRO-seq

    PMID:26474067

    Open questions at the time
    • Exact handoff coordinates from CPSF73 not yet mapped
    • Why histone/snRNA genes show partial dependence unresolved
  12. 2016 High

    Identified CDK9/P-TEFb phosphorylation of XRN2 at Thr439 as a regulatory switch enhancing activity and chromatin loading, linking elongation control kinases to termination.

    Evidence Chemical-genetic substrate ID, in vitro kinase assay, phospho-mutant mutagenesis, ChIP and nascent RNA analysis

    PMID:26728557

    Open questions at the time
    • Whether phosphorylation alters substrate affinity vs catalysis not dissected
    • Additional regulatory phosphosites unexplored
  13. 2016 High

    Provided the structural basis for XTBD-mediated XRN2 stabilization, showing the domain bridges two XRN2 lobes and that a single residue mutation abolishes the complex and phenocopies the null.

    Evidence X-ray crystallography, in vitro binding, mutagenesis and C. elegans complementation

    PMID:26779609

    Open questions at the time
    • Did not resolve full-length XRN2 catalytic architecture
    • Functional consequence of stabilization on individual substrates not mapped
  14. 2016 Medium

    Linked XRN2 to genome maintenance—its loss elevates R-loops, drives DSBs at transcriptional pause sites, and delays DSB repair, integrating its RNA-processing role with DNA stability.

    Evidence IF/co-localization with 53BP1, S9.6 R-loop detection, comet/γH2AX assays and clonogenic survival

    PMID:27437695

    Open questions at the time
    • No in vitro reconstitution of R-loop resolution by XRN2
    • Direct vs indirect contribution to repair unresolved
  15. 2017 High

    Assembled XRN2 into an NKRF/DHX15 pre-ribosomal subcomplex that binds pre-rRNA spacers and executes the early A' cleavage step, mechanistically grounding the rRNA processing role.

    Evidence Co-IP, CRAC, siRNA knockdown, Northern blotting and sucrose gradients

    PMID:28115624

    Open questions at the time
    • Catalytic basis of A' cleavage by XRN2 vs accessory factors unclear
    • Coordination with DHX15 helicase activity undefined
  16. 2018 High

    Used rapid conditional depletion and CPSF73 epistasis to establish that genome-wide XRN2-dependent termination strictly requires prior CPSF73 cleavage, while CPSF73 has a more foundational role and XRN2 is dispensable at histone/snRNA genes.

    Evidence Auxin-inducible degron depletion, mNET-seq and catalytic-inactive CPSF73 complementation

    PMID:29432121

    Open questions at the time
    • What terminates histone/snRNA genes independently of XRN2 unresolved
    • Residual readthrough mechanisms not defined
  17. 2019 Medium

    Distinguished XRN2-dependent early termination from exosome activity, showing XRN2 has little role on DIS3/EXOSC10 substrates.

    Evidence Auxin-inducible degron rapid depletion with RNA-seq and PRO-seq

    PMID:30840897

    Open questions at the time
    • Single lab
    • Partition of substrates between torpedo and exosome incompletely mapped
  18. 2020 Medium

    Mapped XRN2 R-loop substrates genome-wide and showed its loss causes R-loop gains preferentially at termination sites of highly transcribed genes, distinguishing it from DDX5/PRMT5.

    Evidence DRIP-seq with siRNA knockdown

    PMID:32747416

    Open questions at the time
    • Single lab
    • Whether R-loop resolution is degradative or via partner helicases not established
  19. 2020 Medium

    Connected XRN2 R-loop resolution to DSB repair pathway choice, showing it is required for Ku70 loading and NHEJ initiation and supports HR independently of R-loops.

    Evidence siRNA knockdown, RNaseH1 overexpression, Ku70 ChIP and DR-GFP/EJ5-GFP reporters

    PMID:32645903

    Open questions at the time
    • Direct physical contribution of XRN2 to repair complexes unclear
    • Single lab
  20. 2020 Medium

    Defined an XRN2 interactome with DNA repair/replication machinery and revealed a synthetic-lethal relationship with PARP1 inhibition, suggesting therapeutic context.

    Evidence TAP-MS, Co-IP, PARP1 activity assay, KD with clonogenic survival

    PMID:32859985

    Open questions at the time
    • Direct vs indirect interactions with Ku/DNA-PKcs/MCM not dissected
    • Single lab
  21. 2022 High

    Trapped XRN2 loading sites with a catalytic-dead mutant, pinpointing handoff ~2–20 nt downstream of CPSF73 (and RNase Z) cleavage and revealing pervasive promoter-proximal premature termination by the torpedo.

    Evidence 5'-PO4 nascent RNA mapping with Xrn2 D235A, eNET-seq, ChIP and PRO-seq

    PMID:36396340

    Open questions at the time
    • Structural basis of the physical handoff not resolved
    • How XRN2 distinguishes sense vs antisense promoter substrates unclear
  22. 2022 High

    Showed conformational dynamics around the XRN2 catalytic center, modulated by substrate and Mg2+, are intrinsic to catalysis—linking enzyme flexibility to activity.

    Evidence 19F and methyl-TROSY NMR with in vitro degradation assays and mutagenesis

    PMID:36008487

    Open questions at the time
    • Dynamics studied in isolation, not in the termination complex
    • Coupling of dynamics to phospho-regulation not examined
  23. 2022 Medium

    Defined a role for XRN2 in alternative polyadenylation, recruiting Sam68 to compete with CPSF and promote proximal poly(A) site usage and 3' UTR shortening.

    Evidence Co-IP, RIP, CLIP-seq, KD and poly(A)-seq

    PMID:36344846

    Open questions at the time
    • Mechanism of CPSF competition not structurally defined
    • Single lab
  24. 2022 Medium

    Identified CAPRIN1 as a factor that recruits nuclear XRN2 into RNA granules to degrade developmental transcripts during ESC differentiation, extending XRN2 substrate targeting to development.

    Evidence CAPRIN1 knockout, RIP-seq, SLAM-seq, Co-IP interactome and IF co-localization

    PMID:36495875

    Open questions at the time
    • Whether targeting is catalytic torpedo-like or processive decay unclear
    • Single lab
  25. 2023 Medium

    Added a ubiquitin-dependent recruitment layer—RNF8 ubiquitylates XRN2 to drive its occupancy at R-loop-prone loci, with loss promoting transcription-replication collisions in BRCA1-mutant cells.

    Evidence Co-IP, ubiquitylation assays, ChIP, DRIP and a mouse mammary tumor model

    PMID:37697435

    Open questions at the time
    • Ubiquitylated residues and chain type not defined
    • Single lab
  26. 2024 Medium

    Provided structural views of the conserved Rat1/Xrn2-Rai1-Rtt103 torpedo complex across species, revealing a conserved core with variable accessory interfaces.

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

    PMID:39657659

    Open questions at the time
    • Limited functional mutagenesis validation
    • Human complex architecture not directly determined
  27. 2025 Medium

    Established that XRN2 mediates constitutive rapid decay of hypomodified tRNAs—m7G-deficient tRNAs (METTL1 loss) and m1A-deficient tRNA-iMet (TRMT6/61A loss)—as a conserved tRNA surveillance pathway.

    Evidence siRNA/conditional depletion with time-resolved tRNA decay kinetics and Drosophila/human genetic epistasis (preprints)

    PMID:42239164 PMID:bio_10.1101_2025.11.05.686800

    Open questions at the time
    • Preprint status, single labs
    • How XRN2 senses hypomodification not defined
  28. 2025 Medium

    Identified the HELQ helicase as a partner coordinating ATP-dependent R-loop unwinding with XRN2 RNA digestion, refining the molecular logic of R-loop resolution.

    Evidence Co-IP, in vitro helicase/exonuclease assays and cellular R-loop detection

    PMID:39965657

    Open questions at the time
    • Single lab
    • Stoichiometry and order of helicase-exonuclease action not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How XRN2's many recruitment factors (p54nrb/PSF, hnRNPK, CAPRIN1, NKRF, RNF8) and modifications (CDK9 phosphorylation, ubiquitylation) are integrated to select among its diverse substrate classes—termination, rRNA, tRNA, miRNA, R-loops, APA—remains unresolved.
  • No unified model linking partner choice to substrate specificity
  • Structure of the human torpedo complex on a Pol II substrate not determined
  • Whether catalysis vs scaffolding dominates each non-termination role is unclear

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:0005730 nucleolus 4 GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-73894 DNA Repair 3 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
CAPRIN1CDKN2AIP/CARFCPSF73HNRNPKNKRFP54NRB/NONORNF8SENATAXIN/SETX
Complex memberships
NKRF-DHX15-XRN2 pre-ribosomal subcomplexXTBD-XRN2 stabilization complex (PAXT-1/NKRF/CARF)Xrn2/Rat1-Rai1-Rtt103 torpedo complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 XRN2 acts as a 5'→3' exonuclease 'torpedo' that degrades the downstream RNA product of co-transcriptional cleavage (CoTC) at the beta-globin gene, resulting in transcriptional termination by RNA Pol II. The CoTC autocatalytic RNA provides a free 5' end that XRN2 recognizes to degrade the nascent transcript and chase down Pol II. siRNA knockdown of XRN2, in vitro transcription/cleavage assays, nuclear run-on assays Nature High 15565158
2007 XRN2 physically associates with p54nrb/PSF and 3'-processing factors, accumulates at the 3' end of transcribed genes, and is recruited to the 3'-processing machinery via p54nrb/PSF. In vitro, XRN2 degrades the downstream RNA after poly(A) site cleavage (but is not required for the cleavage itself), and degradation is stimulated when coupled to cleavage. p54nrb knockdown reduces XRN2 recruitment and causes termination defects. Co-immunoprecipitation, in vitro 3'-processing assays, ChIP, siRNA knockdown Genes & development High 17639083
2011 Senataxin resolves R-loop structures (RNA/DNA hybrids) that form behind elongating Pol II over G-rich pause sites downstream of poly(A) signals, and this resolution is required for XRN2 to access the 3' cleavage product and degrade it to promote Pol II termination. siRNA knockdown of senataxin and XRN2, R-loop immunofluorescence, nuclear run-on, ChIP Molecular cell High 21700224
2010 XRN2 plays a major role in mammalian pre-rRNA maturation (generating 5' ends of 5.8S and 28S rRNAs) and in degradation of aberrant/discarded pre-rRNA species via 5'→3' exonuclease activity. siRNA knockdown causes accumulation of precursors with 5' extensions. siRNA knockdown of Xrn2 in mouse cells, Northern blotting, primer extension analysis Nucleic acids research High 21036871
2012 Decapping proteins Edc3, Dcp1a, and Dcp2 and the termination factor TTF2 co-immunoprecipitate with XRN2. Knockdown of decapping factors or XRN2/TTF2 redistributes Pol II away from the TSS toward upstream and downstream distal positions, indicating that coupled decapping of nascent transcripts and XRN2-mediated premature termination limits bidirectional Pol II elongation. Co-immunoprecipitation, ChIP-seq, siRNA knockdown Molecular cell High 22483619
2012 Microprocessor (Drosha/Dgcr8) orchestrates recruitment of Setx and XRN2 to the HIV-1 promoter. Cleavage of the stem-loop RNA TAR initiates RNAPII pausing and premature termination at the HIV-1 promoter, with XRN2 acting cooperatively with Rrp6 downstream of microprocessor cleavage. ChIP-seq, siRNA knockdown, co-immunoprecipitation, transcriptional reporter assays Cell High 22980978
2012 XRN2 associates with nascent pre-mRNA and co-transcriptionally degrades aberrantly processed pre-mRNAs (e.g., splicing or 3'-processing mutants). XRN2 also degrades many endogenous pre-mRNAs when processing is inhibited by Spliceostatin A. ChIP, RNA immunoprecipitation, siRNA knockdown, RT-PCR, Northern blotting The EMBO journal Medium 22522706
2015 XRN2 uses a torpedo mechanism that operates genome-wide: a dominant-negative catalytically inactive Xrn2 mutant delayed termination at most poly(A) sites and some histone and snRNA genes. Kinetic competition between XRN2 exonuclease and Pol II elongation rate determines the location of termination—slow elongation shifts termination upstream and fast elongation extends it downstream. Dominant-negative XRN2 mutant expression, Pol II rate mutants, PRO-seq/GRO-seq genome-wide nascent RNA profiling Molecular cell High 26474067
2016 CDK9 (P-TEFb) phosphorylates XRN2 at Thr439 in vivo and in vitro. This phosphorylation enhances XRN2 enzymatic activity on synthetic substrates. Mutation of Thr439 to alanine (non-phosphorylatable) impairs XRN2 chromatin localization and increases readthrough transcription, phenocopying CDK9 inhibition. Chemical genetic substrate identification, in vitro kinase assay with purified proteins, phosphomimetic/phospho-null mutagenesis, ChIP, nascent RNA analysis Genes & development High 26728557
2016 XRN2 undergoes DNA damage-inducible nuclear re-localization, co-localizing with 53BP1 and R-loops in a transcription- and R-loop-dependent process. XRN2 loss leads to increased R-loops, genomic instability, replication stress, DSBs, and hypersensitivity to DNA damaging agents. DSBs from XRN2 loss occur at transcriptional pause sites, and XRN2-deficient cells show an R-loop- and transcription-dependent delay in DSB repair after ionizing radiation. Immunofluorescence, co-localization microscopy, R-loop detection (S9.6 antibody), siRNA knockdown, comet assay, gamma-H2AX staining, clonogenic survival assays PLoS genetics Medium 27437695
2018 Conditional depletion of XRN2 via gene editing reveals a clear general role in cotranscriptional degradation of 3'-flanking region RNA and transcriptional termination genome-wide. XRN2's effect on termination requires prior RNA cleavage by CPSF73. XRN2 plays no significant role in histone or snRNA gene termination. CPSF73 loss causes more extensive readthrough than XRN2 loss, indicating CPSF73 has a more foundational role. Auxin-inducible degron conditional depletion, mNET-seq genome-wide, catalytically inactive CPSF73 complementation Genes & development High 29432121
2014 XRN2 protects HCV RNA from degradation in the cytoplasm is counteracted by miR-122: Xrn2 depletion increases HCV RNA accumulation, while overexpression diminishes it by affecting viral RNA stability (not translation or replication). During miR-122 sequestration, Xrn2 depletion restored HCV RNA abundance. siRNA knockdown, overexpression, luciferase reporter assays, RNA stability measurements Cell host & microbe Medium 25121753
2017 NKRF (NF-κB repressing factor) forms a pre-ribosomal subcomplex with DHX15 and XRN2, binds transcribed spacer regions of pre-rRNA (shown by CRAC), recruits XRN2 to nucleolar pre-ribosomal complexes, and is required for an early pre-rRNA cleavage step (A'). Depletion of NKRF or XRN2 impairs A' cleavage and causes accumulation of excised pre-rRNA spacer fragments. Co-immunoprecipitation, UV crosslinking and cDNA analysis (CRAC), siRNA knockdown, Northern blotting, sucrose gradient sedimentation Nucleic acids research High 28115624
2014 In C. elegans, PAXT-1 (R05D11.6) stabilizes XRN2 protein levels and is required for miRNA turnover activity. A truncated PAXT-1 retaining only the DUF3469/XTBD domain suffices to restore viability, elevate XRN2 levels, and bind XRN2. Human CDKN2AIP/CARF and NKRF interact with XRN2 through this same XTBD domain. TALEN-mediated genome editing, co-immunoprecipitation, western blotting, worm survival assays, in vivo complementation Molecular cell High 24462208
2016 The XTBD (XRN2-binding domain) from PAXT-1 stably interconnects two XRN2 domains through numerous interacting residues (crystal structure). Mutation of a single critical residue disrupts XTBD-XRN2 complexes in vitro and recapitulates paxt-1-null phenotypes in vivo. Vertebrate XTBD-containing proteins (CDKN2AIPNL) bind XRN2 in vitro and can substitute for PAXT-1 in C. elegans. In the absence of substrate, complex formation with PAXT-1 serves to preserve XRN2 stability. X-ray crystallography, in vitro binding assays, site-directed mutagenesis, C. elegans genetic complementation Nature structural & molecular biology High 26779609
2012 In Tetrahymena, the Piwi protein Twi12 binds mature 3' tRNA fragments and assembles a complex with nuclear exonuclease Xrn2. Twi12 stabilizes and localizes Xrn2 to the nucleus, and stimulates its exonuclease activity. Loss of Twi12 or Xrn2 causes rRNA processing defects. Twi12 sRNA binding is required for nuclear import of the complex. Co-immunoprecipitation, sRNA sequencing, ribosome profiling, northern blotting, localization studies, Xrn2 activity assays Molecular cell High 23084833
2015 CARF (collaborator of ARF) directly associates with XRN2 and regulates its subcellular distribution: CARF overexpression increases XRN2 in the nucleoplasm and suppresses pre-rRNA processing, causing accumulation of 5'-extended 45S/47S pre-rRNA; CARF knockdown increases XRN2 in the nucleolar fraction. This phenocopies XRN2 knockdown in the nucleolus. Co-immunoprecipitation, cell fractionation, immunocytochemistry, western blotting, northern blotting, siRNA knockdown/overexpression Nucleic acids research Medium 26531822
2013 hnRNPK co-immunoprecipitates with XRN2 in nuclear extracts; hnRNPK knockdown decreases XRN2 recruitment along EGR1 and downstream of its poly(A) signal (ChIP-seq), and increases pre-RNA read-through downstream of the EGR1 polyadenylation site, suggesting hnRNPK recruits XRN2 to gene loci to regulate termination. ChIP-seq, siRNA knockdown, co-immunoprecipitation with mass spectrometry, RT-PCR The Journal of biological chemistry Medium 23857582
2019 Rapid depletion of XRN2 (using degron technology) reveals that XRN2 loss uncovers different mechanisms for early termination of transcription from protein-coding gene promoters, and that XRN2 has little activity on exosome (DIS3/EXOSC10) substrates. Auxin-inducible degron rapid protein depletion, RNA-seq, PRO-seq Cell reports Medium 30840897
2022 XRN2 is recruited to preinitiation complexes and travels to 3' gene ends. Mapping of 5'-PO4 ends using catalytically inactive Xrn2(D235A) shows XRN2 loading sites ~2–20 bases downstream of CPSF73 cleavage at polyA sites and histone 3' ends, indicating handoff from CPSF73 to XRN2. A similar handoff occurs at tRNA 3' ends after RNase Z cleavage. XRN2 also degrades sense and antisense nascent RNA within a few bases of the TSS, revealing widespread promoter-proximal premature termination by the torpedo mechanism. 5'-PO4 nascent RNA mapping with active-site mutant (Xrn2 D235A), eNET-seq, ChIP, PRO-seq Genes & development High 36396340
2022 NMR studies reveal that Xrn2 is highly dynamic around its catalytic center in the apo state, and substrate plus magnesium shifts the conformational equilibrium toward an active state. A mutation that attenuates these dynamics also reduces catalytic activity, establishing that conformational dynamics are integral to the catalytic mechanism. Fluorine and methyl-TROSY NMR spectroscopy, in vitro RNA degradation assays, mutagenesis Nature chemical biology High 36008487
2023 RNF8 ubiquitylates XRN2, facilitating its recruitment to R-loop-prone genomic loci. RNF8 deficiency decreases XRN2 occupancy at R-loop-prone sites, promoting R-loop accumulation and transcription-replication collisions, leading to genomic instability in BRCA1-mutant cells. Co-immunoprecipitation, ubiquitylation assays, ChIP, R-loop detection (DRIP), genome stability assays, mouse mammary tumorigenesis model Nucleic acids research Medium 37697435
2020 XRN2-mediated R-loop resolution is required for Ku70 binding to DNA ends and initiation of NHEJ repair. XRN2 loss also decreases homologous recombination repair, but this is not restored by RNaseH1 overexpression, indicating that unregulated transcription (not just R-loops) inhibits HR. siRNA knockdown, RNaseH1 overexpression, Ku70 ChIP, DR-GFP and EJ5-GFP HR/NHEJ reporter assays Cancers Medium 32645903
2020 Genome-wide DRIP-seq reveals that XRN2 depletion causes hundreds to thousands of R-loop gains preferentially at highly transcribed genes at transcription termination sites. XRN2, DDX5, and PRMT5 share many R-loop gain loci at termination sites, but DDX5 has unique R-loop gain peaks near TSS not overlapping siXRN2, indicating distinct roles. DRIP-seq (genome-wide R-loop mapping), siRNA knockdown Life science alliance Medium 32747416
2016 In fission yeast, Dhp1/Xrn2 cooperates with RNA elimination factors to promote premature termination at meiotic genes and facilitate facultative heterochromatin formation. Dhp1 also interacts with the Clr4/Suv39h methyltransferase complex and acts directly to nucleate heterochromatin. Genetic epistasis, ChIP, co-immunoprecipitation, reporter gene silencing assays in S. pombe Proceedings of the National Academy of Sciences of the United States of America Medium 26631744
2022 XRN2 promotes recruitment of Sam68 to target transcripts, where the Sam68/XRN2 complex competes with CPSF for binding to strong distal polyadenylation signals, thereby promoting usage of suboptimal proximal polyadenylation signals and 3' UTR shortening. Co-immunoprecipitation, RNA immunoprecipitation, CLIP-seq, siRNA knockdown, poly(A)-seq transcriptome profiling Nature structural & molecular biology Medium 36344846
2016 In C. elegans, Nkx2-5 deficiency affects Xrn2 binding to target loci and results in increased RNAPII occupancy and expression of mRNAs with long 3' UTRs from heart development genes. Genetic interaction (double heterozygous Nkx2-5+/−; Xrn2+/−) causes ventricular septum defects not seen in single heterozygotes, establishing that Nkx2-5 and Xrn2 cooperate in regulating alternative polyadenylation during heart development. ChIP, siRNA knockdown, genetic compound heterozygotes in mice, 3'-seq for APA analysis eLife Medium 27331609
2014 In C. elegans, XRN2 loss of function (null or catalytic-dead) causes molting defect and larval arrest, demonstrating that XRN2 catalytic activity is essential for development. XRN2 has specificity for a subset of miRNAs in vivo—some rapidly decaying miRNAs are stabilized by XRN2 loss while others continue to decay, indicating XRN2-independent decay pathways for certain miRNAs. Conditional allele engineering (temperature-sensitive), null mutation, small RNA sequencing, miRNA stability assays Nucleic acids research Medium 24445807
2015 Nuclear XRN2 degrades the 3' fragments of pre-mRNA generated by RNase H1-mediated cleavage of ASO-targeted transcripts from their 5' ends, while XRN1 is responsible for cytoplasmic mRNA fragment degradation after siRNA-mediated cleavage. siRNA knockdown of XRN1 and XRN2, northern blotting for cleavage fragment detection, nuclear/cytoplasmic fractionation Biochemical and biophysical research communications Medium 26159921
2011 NPGPx covalently binds to XRN2 upon non-targeting siRNA stress and facilitates XRN2-mediated removal of accumulated non-targeting siRNA, relieving cellular stress. Co-immunoprecipitation, covalent crosslinking assay, siRNA accumulation measurement, cell growth assays Nucleic acids research Low 21908404
2022 CAPRIN1 promotes degradation of developmental transcripts during early ESC differentiation via XRN2. Upon differentiation, XRN2 localizes to the nucleus and co-localizes with CAPRIN1 in small RNA granules in a CAPRIN1-dependent manner, identifying CAPRIN1 as a factor that recruits XRN2 to specific RNA targets. CAPRIN1 knockout, RIP-seq, SLAM-seq, XRN2 co-immunoprecipitation/interactome, immunofluorescence co-localization Developmental cell Medium 36495875
2020 XRN2 interacts with DNA repair/replication proteins including Ku70-Ku80, DNA-PKcs, PARP1, and MCM2-7 as shown by tandem affinity purification-mass spectrometry. XRN2 depletion hyperactivates PARP1 activity, and combined XRN2 depletion and PARP1 inhibition results in synthetic lethality. Tandem affinity purification-mass spectrometry (TAP-MS), Co-IP, PARP1 activity assay, siRNA knockdown, clonogenic survival, flow cytometry Scientific reports Medium 32859985
2023 XRN2 regulates TERRA RNA stability; XRN2 depletion in ALT-positive cancer cells increases TERRA R-loops and exacerbates ALT activity, establishing XRN2 as a key determinant of TERRA metabolism at telomeres. siRNA knockdown, northern blotting for TERRA, DRIP-qPCR for R-loops, ALT-associated PML body foci quantification FEBS letters Low 37191774
2024 Structural characterization of the Xrn2/Rat1-Rai1-Rtt103 torpedo termination complex from S. cerevisiae and C. thermophilum reveals conserved protein core folds but variable interaction interfaces: in the mesophile, Rtt103 uses an unstructured region to augment a Rai1 β-sheet, while in the thermophile Rtt103 binds a C-terminal Rai1 helix via a CTD-interacting domain with α-helical fold. Cryo-EM, X-ray crystallography, structural biology Structure Medium 39657659
2020 Full-length NKRF contains an N-terminal XTBD (XRN2-binding domain) encoded from an alternative upstream AUG start codon; this XTBD is essential for XRN2 retention in the nucleolus. NKRF is tethered in the nucleolus by binding rRNA and controls spatial distribution of XRN2 between nucleoplasm and nucleolus to regulate early pre-rRNA processing. Alternative start codon identification, co-immunoprecipitation, immunofluorescence, subcellular fractionation, domain deletion mutagenesis The Biochemical journal Medium 32011671
2025 HELQ helicase interacts with XRN2 and cooperates with it in R-loop resolution: HELQ unwinds R-loops (requires ATPase activity) and is functionally coordinated with XRN2-mediated RNA digestion, shown both in cells and in vitro. Co-immunoprecipitation, in vitro helicase and exonuclease assays, R-loop detection in cells, siRNA/inhibitor experiments Open biology Medium 39965657
2026 XRN2 degrades hypomethylated (m1A-lacking) tRNA-iMet in human cells: acute loss of TRMT6/61A leads to rapid XRN2-dependent degradation of tRNA-iMet, reducing global protein synthesis. XRN2 inhibition rescues tRNA-iMet levels and reverses growth defects in TRMT6/61A-depleted cells. dTAG rapid depletion system, tRNA-seq, pulse-chase tRNA stability measurements, XRN2 knockdown/inhibition complementation assays bioRxivpreprint Medium 42239164
2025 XRN2 mediates accelerated decay of m7G-hypomodified tRNAs under physiological (non-stress) conditions: XRN2 knockdown restores tRNA levels diminished by METTL1 depletion. Partial loss of Drosophila XRN2 ortholog Rat1 genetically rescues male sterility of mettl1 mutants, establishing a conserved constitutive rapid tRNA decay pathway. siRNA knockdown of XRN2, conditional protein knockdown with time-resolved tRNA decay kinetics, Drosophila genetic epistasis bioRxivpreprint Medium bio_10.1101_2025.11.05.686800
2017 XRN2 accelerates maturation of pre-miR-10a by binding to the precursor miRNA in a DICER-independent manner, promoting its maturation and thereby inducing EMT and metastasis in lung cancer. Co-immunoprecipitation/pulldown of XRN2 with pre-miR-10a, in vitro processing assays, overexpression and knockdown, in vivo metastasis assays Oncogene Low 28319071

Source papers

Stage 0 corpus · 56 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 677 21700224
2004 Human 5' --> 3' exonuclease Xrn2 promotes transcription termination at co-transcriptional cleavage sites. Nature 390 15565158
2015 Effects of Transcription Elongation Rate and Xrn2 Exonuclease Activity on RNA Polymerase II Termination Suggest Widespread Kinetic Competition. Molecular cell 175 26474067
2012 mRNA decapping factors and the exonuclease Xrn2 function in widespread premature termination of RNA polymerase II transcription. Molecular cell 175 22483619
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 150 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
2018 Xrn2 accelerates termination by RNA polymerase II, which is underpinned by CPSF73 activity. Genes & development 103 29432121
2014 Hepatitis C virus subverts liver-specific miR-122 to protect the viral genome from exoribonuclease Xrn2. Cell host & microbe 103 25121753
2016 XRN2 Links Transcription Termination to DNA Damage and Replication Stress. PLoS genetics 98 27437695
2010 5'-end surveillance by Xrn2 acts as a shared mechanism for mammalian pre-rRNA maturation and decay. Nucleic acids research 79 21036871
2012 Co-transcriptional degradation of aberrant pre-mRNA by Xrn2. The EMBO journal 78 22522706
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
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 60 28115624
2015 Dissecting the roles of the 5' exoribonucleases Xrn1 and Xrn2 in restricting hepatitis C virus replication. Journal of virology 58 25673723
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
2020 Genome-wide R-loop analysis defines unique roles for DDX5, XRN2, and PRMT5 in DNA/RNA hybrid resolution. Life science alliance 57 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 31 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
2023 RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells. Nucleic acids research 21 37697435
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
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
2020 XRN2 Links RNA:DNA Hybrid Resolution to Double Strand Break Repair Pathway Choice. Cancers 16 32645903
2018 An end in sight? Xrn2 and transcriptional termination by RNA polymerase II. Transcription 16 30035655
2016 Structural basis and function of XRN2 binding by XTB domains. Nature structural & molecular biology 16 26779609
2022 RNA degradation eliminates developmental transcripts during murine embryonic stem cell differentiation via CAPRIN1-XRN2. Developmental cell 15 36495875
2020 XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition. Scientific reports 14 32859985
2016 XRN2 Autoregulation and Control of Polycistronic Gene Expresssion in Caenorhabditis elegans. PLoS genetics 13 27631780
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 12 39893168
1999 Cloning and mapping of the XRN2 gene to human chromosome 20p11.1-p11.2. Genomics 12 10409438
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 8 32011671
2022 XRN2 Is Required for Cell Motility and Invasion in Glioblastomas. Cells 7 35563787
2025 Nsclc-derived exosomal hsa_circ_0003026 promotes tumor growth through macrophage M2 polarization via hsa-miR-1183/XRN2 axis. Gene 6 40345505
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
2026 TRMT6/61A-mediated m 1 A methylation facilitates human pre-tRNA maturation and prevents surveillance by XRN2. bioRxiv : the preprint server for biology 0 42239164
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

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