Affinage

WRN

Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN · UniProt Q14191

Length
1432 aa
Mass
162.5 kDa
Annotated
2026-06-11
100 papers in source corpus 49 papers cited in narrative 49 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

WRN is a multifunctional RecQ-family DNA helicase/exonuclease that directs its catalytic activities to stalled and collapsed replication forks, recombination intermediates, and telomeres to preserve genome stability (PMID:11256630, PMID:17717003, PMID:12427008). Its core 3′→5′ helicase and 3′→5′ exonuclease activities act on Holliday junctions, D-loops, replication forks, cruciforms, and G-quadruplexes, catalyzing ATP-dependent fork regression and strand annealing (PMID:11256630, PMID:12427008, PMID:17717003, PMID:36541070); single-molecule analyses show WRN unwinds by reciprocating along ssDNA with limited intrinsic processivity, but multiple RPA molecules convert it into a unidirectional 'superhelicase' capable of unwinding >1 kb (PMID:28266653, PMID:29668972). WRN activity is shaped by an extensive partner network that targets it to specific substrates: RPA and XPG stimulate its helicase at stalled forks (PMID:11256630, PMID:21558802), POT1 and TRF2 stimulate telomeric helicase/exonuclease and strand exchange (PMID:16030011, PMID:14712220, PMID:24880691), Ku70/80 stimulates the exonuclease at DSB ends (PMID:16622405), and p53 inhibits the helicase (PMID:15735006). At replication forks and DSBs WRN coordinates end resection by acting epistatically with DNA2 to drive long-range 5′→3′ resection for homologous recombination, while also resecting the 5′ ends of ssDNA gaps through a distinct MRN-CtIP-independent route (PMID:25122754, PMID:40127955); it additionally serves non-enzymatic structural roles, stabilizing RAD51 and shielding nascent strands and DSBs from MRE11/CtIP to promote classical NHEJ and suppress alternative NHEJ (PMID:25456133, PMID:26275776, PMID:27922005). Deployment is orchestrated by post-translational modification: ATR phosphorylation at S1141 drives ubiquitin-proteasomal turnover (PMID:26695548), ATM phosphorylation enables RAD51 recruitment (PMID:20802463), CDK1 phosphorylation at S1133 licenses MRE11 interaction and DNA2 resection (PMID:27634057), CDK2 phosphorylation at S426 tunes RPA affinity and DSB pathway choice (PMID:34612580), and CBP/p300 acetylation (reversed by SIRT1) regulates activity, localization, and MDM2-dependent stability (PMID:18203716, PMID:20428248, PMID:30532073). In microsatellite-instable cancers WRN helicase is selectively essential to unwind expanded TA-dinucleotide-repeat cruciform/non-B structures that, absent WRN, are cleaved by MUS81 to cause chromosome shattering, establishing WRN as a synthetic-lethal target now drugged by allosteric covalent helicase inhibitors that lock it in an inactive conformation (PMID:30971823, PMID:32999459, PMID:38658754, PMID:38658751).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1999 High

    Established that WRN helicase is not an autonomous enzyme but is functionally coupled to the single-strand binding protein RPA, defining the first key cofactor that enables long-range unwinding.

    Evidence Co-IP of purified proteins and in vitro helicase assays on long duplex substrates comparing RPA to bacterial/phage SSBs

    PMID:10373438

    Open questions at the time
    • Did not resolve stoichiometry or the conformational basis of RPA stimulation
    • No cellular demonstration of the interaction at forks
  2. 2002 High

    Defined WRN's substrate repertoire beyond simple duplexes by showing it disrupts D-loops, stimulates FEN-1 flap cleavage, and operates within an RNA polymerase I complex, linking it to recombination, Okazaki processing, and rRNA transcription.

    Evidence In vitro biochemistry on D-loop and flap substrates; co-IP with RPI subunit RPA40 and complementation of WS fibroblasts

    PMID:11971179 PMID:12356323 PMID:12427008

    Open questions at the time
    • Relative physiological weighting of these activities unresolved
    • Nucleolar role mechanistically distinct from fork roles
  3. 2003 High

    Distinguished WRN's catalytic from structural contributions to repair, showing a non-enzymatic scaffolding role in NHEJ/HR optimization separable from helicase/exonuclease activity, and a functional RAD52 interaction at forks.

    Evidence Complementation of WRN-null cells with enzymatic-dead mutants in NHEJ/HR assays; in vivo FRET and in vitro reconstitution with RAD52

    PMID:12750383 PMID:12934712

    Open questions at the time
    • Molecular basis of the structural role not defined at this stage
    • Which DSB substrates require scaffolding vs catalysis unclear
  4. 2004 High

    Identified telomere- and DSB-specific recruiters that target WRN's exonuclease, showing TRF2 directs WRN to telomeric substrates and Ku70/80 to DNA ends.

    Evidence DNA-independent pulldowns and in vitro exonuclease assays on telomeric substrates (TRF2); later crystallographic work with Ku70/80 stimulation

    PMID:14712220

    Open questions at the time
    • In vivo consequences of TRF2-directed exonuclease not yet established
    • Selectivity of stimulation for exonuclease over helicase not mechanistically explained
  5. 2006 High

    Provided the structural and catalytic basis of the WRN exonuclease, defining a two-metal-ion DnaQ-family proofreading mechanism and confirming Ku70/80 stimulation and a role in cellular end joining.

    Evidence X-ray crystallography of metal-ion complexes plus active-site mutagenesis, in vitro exonuclease assays, and DNA end-joining assays in human cells

    PMID:16622405

    Open questions at the time
    • Structure of the helicase domain and full-length enzyme not solved here
    • How exonuclease and helicase domains are coordinated unresolved
  6. 2007 High

    Demonstrated WRN catalyzes ATP-dependent replication fork regression with its exonuclease shaping the substrate, mechanistically placing WRN in the protection and remodeling of stalled forks.

    Evidence In vitro fork regression assays on model substrates comparing wild-type and exonuclease-deficient WRN

    PMID:17717003

    Open questions at the time
    • In vivo regulation of fork regression by WRN not addressed
    • Coordination with other fork-remodeling enzymes unknown
  7. 2008 High

    Revealed acetylation as a major regulatory layer, with CBP/p300 acetylation tuning WRN activity and localization and SIRT1 reversing it, while also placing WRN in long-patch BER, ATM checkpoint activation, and alt-NHEJ in CML.

    Evidence Acetylation/deacetylation and activity assays; HDAC-inhibitor BER epistasis; RNAi with ATM-target phosphorylation readouts; co-IP with DNA ligase IIIα in CML cells

    PMID:18203716 PMID:18212065 PMID:18398454 PMID:18524993 PMID:18596239

    Open questions at the time
    • Causal hierarchy among acetylation, localization, and activity changes incompletely ordered
    • Context dependence of pro- vs anti-recombinogenic roles unresolved
  8. 2009 Medium

    Placed WRN in the cellular response to oncogene-driven replication stress, showing its loss converts c-Myc-accelerated S-phase into ATR–CHK1–p53 signaling and senescence.

    Evidence WRN siRNA in c-Myc-overexpressing fibroblasts with γ-H2AX/BrdU staining and pathway inhibitor and p53 rescue analysis

    PMID:19554081

    Open questions at the time
    • Direct DNA substrate engaged under oncogenic stress not defined
    • Single cell system without biochemical reconstitution
  9. 2010 High

    Defined the kinase control of WRN's fork localization and stability, with ATR/ATM phosphorylation governing focus formation, RPA co-localization, and RAD51 recruitment, and established further telomeric (POT1) and fork (DHX9) cofactors plus exonuclease limits at oxidative lesions.

    Evidence ATR/ATM-unphosphorylatable alleles with fiber and focus assays; in vitro helicase stimulation by POT1 and DHX9; exonuclease assays on 3′-blocked substrates; PCNA/NBS1 TLS co-IPs

    PMID:16030011 PMID:17224176 PMID:20385589 PMID:20600238 PMID:20802463 PMID:21123451

    Open questions at the time
    • Site-resolved ATR/ATM target residues not fully mapped at this stage
    • Integration of multiple kinase inputs not yet unified
  10. 2011 High

    Identified XPG as a direct C-terminal partner that stimulates WRN helicase and cooperates in strand annealing at stalled forks, expanding the fork-associated WRN interactome.

    Evidence Co-IP, domain mapping, in vitro helicase/annealing assays, and S-phase co-localization

    PMID:21558802

    Open questions at the time
    • Physiological pathway in which WRN-XPG operates not defined in cells
    • Whether XPG nuclease activity is involved unaddressed
  11. 2014 High

    Resolved WRN's role in DSB end resection, showing it acts with DNA2 for RPA-dependent long-range resection (with CDK1-phospho-S1133 enabling MRE11 interaction) while also non-enzymatically protecting nascent strands via NBS1 recruitment.

    Evidence siRNA epistasis, WRN-DNA2 co-IP, in vitro resection with purified proteins, DNA fiber assays, NBS1-FHA domain mapping, catalytic-mutant analysis

    PMID:25122754 PMID:25456133

    Open questions at the time
    • Switch between resection-promoting and strand-protecting modes not fully defined
    • Relative contributions of WRN catalysis vs DNA2 unclear in vivo
  12. 2015 High

    Separated the opposing domain functions at perturbed forks, showing the WRN exonuclease protects nascent strands from MRE11/EXO1 degradation while the helicase enables proper exonucleolytic processing downstream of RAD51.

    Evidence Domain-specific mutant analysis with DNA fiber assays and MRE11/EXO1/RAD51 epistasis

    PMID:26275776

    Open questions at the time
    • How the two domains are temporally coordinated at a single fork unresolved
    • Regulatory signal selecting protection vs processing not identified
  13. 2016 High

    Established WRN as an arbiter of DSB pathway choice and detailed the phospho-regulation underlying it, promoting classical NHEJ enzymatically while non-enzymatically suppressing alt-NHEJ, with CDK1-S1133 licensing DNA2 resection and ATR-S1141 driving turnover.

    Evidence Knockdown plus enzymatic-mutant complementation, end-resection and MRE11/CtIP recruitment assays, telomere fusion assays, in vitro CDK1 kinase assay with phosphomimetic mutants and ubiquitination assays

    PMID:26695548 PMID:27634057 PMID:27922005

    Open questions at the time
    • Integration of CDK1 and ATR inputs into a single decision model incomplete
    • Cell-cycle timing of pathway switching not fully resolved
  14. 2018 High

    Mechanistically explained how RPA reprograms WRN and how that loading is regulated, showing multiple RPAs create a >1 kb superhelicase, HERC2-mediated RPA2 ubiquitination enables RPA handoff, and MDM2 ubiquitinates WRN to drive p53-independent senescence.

    Evidence Single-molecule FRET and magnetic tweezers; HERC2 E3-dead CRISPR lines with RPA2 ubiquitination and G4 assays; MDM2 co-IP, ubiquitination, stability, and senescence rescue assays

    PMID:29668972 PMID:30279242 PMID:30532073

    Open questions at the time
    • How superhelicase behavior is engaged at specific in vivo substrates unresolved
    • Cross-talk between MDM2 and ATR/acetylation-dependent turnover not unified
  15. 2019 High

    Identified the dependency that makes WRN a cancer target, showing WRN helicase (not exonuclease) is selectively essential in microsatellite-instable cells where its loss triggers DSBs and death.

    Evidence CRISPR/RNAi screens, helicase- vs exonuclease-dead complementation, and in vivo xenografts with damage/apoptosis readouts

    PMID:30971823

    Open questions at the time
    • Molecular nature of the MSI-specific substrate not defined in this study
    • Why helicase but not exonuclease is essential left for follow-up
  16. 2020 High

    Defined the MSI synthetic-lethal mechanism, showing expanded TA-dinucleotide repeats form non-B structures that stall forks and, without WRN unwinding, are cleaved by MUS81 to shatter chromosomes.

    Evidence DNA fiber stalling assays, ATR activation, TA-repeat measurement, MUS81 epistasis, and cytogenetics in isogenic MSI/MSS cells

    PMID:32999459

    Open questions at the time
    • Full spectrum of non-B structures resolved by WRN not enumerated
    • Whether other nucleases contribute to shattering unaddressed
  17. 2021 High

    Extended WRN's fork-protective role to BRCA2-deficient contexts and refined resection pathway choice, showing WRN helicase limits MRE11 degradation of regressed forks and CDK2-S426 phosphorylation stabilizes RPA binding to direct HR.

    Evidence In vitro fork restoration assays, helicase-inhibitor treatment with MRE11/MUS81 epistasis and xenografts; in vitro CDK2 kinase assay with S426 phosphomimetic mutants and RPA co-IP

    PMID:34612580 PMID:34772932

    Open questions at the time
    • How CDK2-S426 and CDK1-S1133 signals are coordinated unresolved
    • In vivo therapeutic window in BRCA2-deficient tumors not fully defined
  18. 2022 High

    Linked WRN's structure-resolving helicase to broader physiology and to anti-nuclease protection, showing it unfolds cruciforms to prevent SLX1-SLX4 cleavage (synergizing with MutLα) and unwinds promoter G-quadruplexes to drive SHOX expression and chondrogenesis.

    Evidence In vitro cruciform/SLX1-SLX4 and combined MutLα assays; WRN-null zebrafish with G4 unwinding assays and SHOX rescue

    PMID:36114168 PMID:36541070

    Open questions at the time
    • Generality of transcriptional G4-resolving role across loci unknown
    • Mechanistic basis of WRN-MutLα synergy not defined
  19. 2024 High

    Delivered structurally defined allosteric WRN inhibitors, showing HRO761 binds the D1-D2 helicase interface and VVD-133214 covalently engages cysteine C727 to lock WRN inactive and selectively kill MSI-H cells.

    Evidence Structural and chemoproteomic characterization, biochemical helicase inhibition, conformational/nucleotide cooperativity studies, and MSI-selective cellular and xenograft validation

    PMID:38658751 PMID:38658754

    Open questions at the time
    • Long-term resistance mechanisms to WRN inhibition not characterized
    • Differential WRN degradation in MSI vs MSS cells mechanistically incomplete
  20. 2025 High

    Distinguished WRN's gap-resection activity from DSB resection, showing DNA2-WRN/BLM resects 5′ ends of ssDNA gaps independently of MRN-CtIP and that excessive resection in BRCA1-deficient cells generates damaging gaps.

    Evidence Single-molecule fiber analysis, electron microscopy, in vitro resection with purified proteins, and MRN-CtIP epistasis in BRCA1-deficient cells

    PMID:40127955

    Open questions at the time
    • How gap vs DSB resection modes are selected in cells unresolved
    • Regulatory inputs controlling the extent of gap resection unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the full set of post-translational signals (ATR/ATM/CDK1/CDK2 phosphorylation, acetylation, MDM2/HERC2 ubiquitination) is integrated in real time to choose among fork regression, gap resection, DSB resection, NHEJ promotion, and degradation at a given lesion remains unresolved.
  • No unified quantitative model linking modification state to substrate choice
  • Structure of full-length WRN engaging physiological substrates lacking
  • Lesion-context determinants of enzymatic vs non-enzymatic deployment undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 5 GO:0003677 DNA binding 4 GO:0098772 molecular function regulator activity 4 GO:0140657 ATP-dependent activity 4 GO:0016787 hydrolase activity 3
Localization
GO:0005654 nucleoplasm 3 GO:0005730 nucleolus 3 GO:0005634 nucleus 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-69306 DNA Replication 4 R-HSA-73894 DNA Repair 4 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-8953854 Metabolism of RNA 2
Partners
DNA2FEN1MDM2NBS1POT1RPATRF2XPG
Complex memberships
Pso4/Prp19 splicing complexRNA polymerase I complex

Evidence

Reading pass · 49 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 WRN helicase physically interacts with human replication protein A (hRPA) via co-immunoprecipitation of purified proteins, and hRPA specifically stimulates WRN helicase to unwind long duplex DNA substrates (up to 849 bp); E. coli SSB and T4 gp32 failed to substitute for hRPA, indicating a specific functional interaction. Co-immunoprecipitation of purified proteins; in vitro helicase assay on long duplex substrates with various SSB proteins The Journal of biological chemistry High 10373438
2000 WRN promotes ATP-dependent translocation of Holliday junctions in vitro and, upon S-phase arrest with hydroxyurea, co-localizes with RPA in discrete nuclear foci, consistent with a role in preventing aberrant recombination at stalled replication forks. In vitro Holliday junction migration assay; immunofluorescence co-localization in hydroxyurea-arrested cells EMBO reports High 11256630
2002 WRN helicase disrupts D-loop structures and its 3′→5′ exonuclease attacks the 3′ end of the inserted strand of D-loops in vitro, implicating WRN in recombination and telomere maintenance pathways that utilize D-loop intermediates. In vitro biochemical assay with model D-loop DNA substrates; helicase and exonuclease activity measurements Biochemistry High 12427008
2002 WRN stimulates FEN-1 cleavage efficiency (rather than DNA substrate binding) on flap substrates including Okazaki fragment-processing intermediates, by a mechanism distinct from PCNA-FEN-1 stimulation; WRN does not require a free upstream end to stimulate FEN-1. In vitro FEN-1 cleavage kinetic assay with streptavidin-blocked substrates; biochemical characterization of WRN-FEN-1 interaction Biochemistry High 12356323
2002 WRN helicase accelerates rRNA transcription as part of an RNA polymerase I (RPI)-associated complex; WRN co-immunoprecipitates with RPA40 (an RPI subunit), WS fibroblasts show reduced rRNA transcription restored by wild-type WRN but not by a nucleolus-targeting-deficient WRN mutant. Co-immunoprecipitation; rRNA transcription assay in WS cells; complementation with wild-type vs. nucleolus-localization-deficient WRN Oncogene High 11971179
2003 WRN plays a structural (non-enzymatic) role in optimizing DNA repair: an exonuclease/helicase double-mutant complements NHEJ and HR deficiencies in WRN-null cells nearly as well as wild-type WRN, whereas single enzymatic mutants show partial complementation, indicating WRN's structural role is separable from its catalytic activities. Complementation assay in WRN-/- cells with enzymatic-dead WRN mutants; NHEJ and HR repair assays Aging cell High 12934712
2003 WRN physically and functionally interacts with the homologous recombination mediator RAD52: FRET shows WRN-RAD52 complex formation in vivo at arrested replication fork foci; RAD52 modulates WRN helicase activity in a DNA-structure-dependent manner, and WRN enhances RAD52-mediated strand annealing. FRET in vivo; co-localization at stalled replication forks; in vitro helicase and strand annealing assays The Journal of biological chemistry High 12750383
2004 TRF2 physically interacts with WRN independently of DNA and recruits WRN exonuclease to telomeric DNA substrates: TRF2 binds telomeric-repeat-containing substrates and specifically stimulates WRN exonuclease (not helicase) activity on them. Direct protein-protein interaction assay (pulldown without DNA); in vitro WRN exonuclease assay on telomeric substrates with/without TRF2 Oncogene High 14712220
2004 APE1 inhibits WRN helicase activity on single-strand break BER intermediates (likely by occupying the AP site), and this inhibition is relieved by DNA polymerase beta (pol β), suggesting a pol β-mediated handoff of WRN during base excision repair. In vitro helicase assay on BER intermediate substrates; addition of APE1 and pol β proteins The Journal of biological chemistry Medium 15385537
2005 POT1 strongly stimulates WRN and BLM to unwind long telomeric forked duplexes and D-loop structures in a telomeric-sequence-dependent manner; POT1 binds directly to WRN and BLM in vitro, and full-length POT1 co-precipitates more WRN than BLM from HeLa nuclear extracts. In vitro helicase unwinding assay on telomeric substrates; pulldown and co-immunoprecipitation from nuclear extracts The Journal of biological chemistry High 16030011
2005 Both WRN and BLM bind the extreme C-terminal 18-amino-acid tail of FEN-1, a site adjacent to (but distinct from) the PCNA-binding site; WRN facilitates FEN-1 binding to its preferred double-flap substrate through this protein interaction, and WRN and PCNA have additive stimulatory effects on FEN-1 activity. Interaction mapping with FEN-1 deletion mutants; functional stimulation assays with WRN + FEN-1 mutants; binding assays Nucleic acids research High 16326861
2005 WRN helicase is inhibited by p53 both in the presence of RPA (on 849-bp M13 substrates) and in the absence of RPA (on short forked duplexes); WRN, RPA, and p53 co-immunoprecipitate in vivo, and p53 inhibits WRN via a binding site on the WRN helicase domain. Co-immunoprecipitation in vivo; in vitro helicase assay with purified WRN, RPA, p53; WRN helicase-domain fragment lacking p53-binding site as control Cancer research High 15735006
2005 The Pso4 mRNA splicing complex (Pso4/Prp19, Cdc5L, Plrg1, Spf27) is required for ICL processing in vitro, physically associates with WRN through a direct WRN–Cdc5L interaction, and WRN helicase (but not exonuclease) activity is required for ICL processing. In vitro ICL processing biochemical assay; co-immunoprecipitation; direct binding assay between WRN and Cdc5L; WRN helicase- and exonuclease-mutant analysis The Journal of biological chemistry High 16223718
2006 Crystal structures of the WRN exonuclease domain reveal a two-metal-ion nuclease mechanism; active-site mutations inactivate the exonuclease; Ku70/80 specifically stimulates WRN exonuclease activity; structure-based WRN-exo mutants alter DNA end joining in human cells. WRN-exo shares structural and mechanistic homology with DnaQ-family replicative proofreading exonucleases. X-ray crystallography (metal-ion complex structures); active-site mutagenesis + in vitro exonuclease assay; Ku70/80 stimulation assay; DNA end-joining assay in human cells with WRN-exo mutants Nature structural & molecular biology High 16622405
2007 WRN catalyzes ATP-dependent replication fork regression and Holliday junction formation in vitro; this is enhanced on forks with single-stranded gaps (≥11–13 nt) on the leading arm, and WRN exonuclease activity promotes regression by digesting the leading daughter strand to create an optimal substrate. In vitro fork regression assay with model replication fork substrates; ATP-dependence assay; comparison of wild-type vs. exonuclease-deficient WRN Nucleic acids research High 17717003
2008 SIRT1 interacts with WRN in vitro and in vivo (interaction enhanced after DNA damage); WRN is acetylated by CBP/p300; SIRT1 deacetylates WRN in vitro and in vivo; WRN acetylation decreases its helicase and exonuclease activities; SIRT1-mediated deacetylation reverses this; acetylation alters WRN nuclear distribution and SIRT1 knockdown reduces WRN translocation from nucleoplasm to nucleoli after DNA damage. Co-immunoprecipitation in vitro and in vivo; acetylation/deacetylation assays; in vitro helicase/exonuclease activity assays on acetylated vs. unacetylated WRN; immunofluorescence for nuclear distribution The Journal of biological chemistry High 18203716
2008 DNA ligase IIIα and WRN form a complex recruited to DSBs in CML cells; knockdown of either protein increases accumulation of unrepaired DSBs; WRN is up-regulated in BCR-ABL-positive CML cells where it participates in an alternative NHEJ pathway. Co-immunoprecipitation; siRNA knockdown with γ-H2AX DSB accumulation readout; recruitment to DSB foci Blood Medium 18524993
2008 p300 acetylates WRN, stimulating its catalytic activities in vitro and in vivo; acetylated WRN enhances pol β-mediated strand displacement synthesis more than unacetylated WRN; sodium butyrate (HDAC inhibitor) stimulates long-patch BER in wild-type but not WRN-depleted cells, placing acetylated WRN in the long-patch BER pathway. In vitro acetylation and helicase/exonuclease activity assays; strand displacement synthesis assay; cellular BER assay with HDAC inhibitor and WRN depletion PloS one High 18398454
2008 WRN is required for ATM pathway activation in response to psoralen ICL-induced DSBs: WRN depletion impairs the intra-S checkpoint, reduces ATM activation and downstream phosphorylation of ATM targets, and increases γ-H2AX levels, indicating WRN facilitates ATM activation at collapsed replication forks. RNAi knockdown of WRN; immunoblot for ATM and ATM-target phosphorylation; S-phase checkpoint (BrdU incorporation); γ-H2AX measurement Molecular biology of the cell Medium 18596239
2008 WRN controls formation of extrachromosomal telomeric circles: WRN helicase is required for TRF2ΔB-mediated telomere shortening via t-loop homologous recombination; both WRN exonuclease and helicase activities are required to suppress spontaneous telomeric circle formation in telomerase-positive WS fibroblasts. Complementation of WS cells with wild-type vs. exonuclease- or helicase-dead WRN mutants; telomeric circle assay; telomere length analysis Molecular and cellular biology High 18212065
2009 WRN is required to repair abnormal replication structures caused by c-Myc-driven S-phase acceleration; depletion of WRN in c-Myc-overexpressing primary human fibroblasts increases DNA damage specifically at replication foci, activating an ATR–CHK1–CHK2–p53 'replication stress' pathway leading to senescence. WRN siRNA depletion in c-Myc-overexpressing fibroblasts; γ-H2AX co-staining with BrdU; pathway inhibitor analysis; p53 rescue experiment PloS one Medium 19554081
2010 ATR directly phosphorylates WRN at multiple C-terminal S/TQ residues; loss of ATR-mediated phosphorylation prevents WRN accumulation in nuclear foci and co-localization with RPA, causing breakage of stalled forks; ATM kinase phosphorylation of WRN is required for RAD51 recruitment and replication recovery after fork collapse. Expression of ATR/ATM-unphosphorylatable WRN alleles; immunofluorescence for WRN foci and RPA co-localization; DNA fiber assay; RAD51 recruitment assay; in vitro kinase assay The EMBO journal High 20802463
2010 BCR-ABL induces WRN tyrosine phosphorylation (through direct complex formation with WRN) and stimulates WRN helicase and exonuclease activities; activated WRN protects BCR-ABL-positive cells from oxidative/genotoxic stress and promotes unfaithful HR and SSA recombination repair. Co-immunoprecipitation of WRN-BCR/ABL complex; tyrosine phosphorylation assay; in vitro helicase/exonuclease activity assays after BCR-ABL stimulation; siRNA knockdown with survival and repair readouts Cancer research Medium 21123451
2010 WRN interacts with PCNA in the absence of DNA damage; DNA damage induces dissociation of PCNA from WRN in an ATM/NBS1-dependent manner, leading to PCNA ubiquitination required for TLS; WRN participates in translesion synthesis through NBS1-FHA-domain-mediated interaction and NBS1-dependent WRN phosphorylation. Co-immunoprecipitation; PCNA ubiquitination assay; nuclear focus formation; epistasis with NBS1-FHA domain mutants Mechanisms of ageing and development Medium 20600238
2010 DHX9 (RNA helicase A) stimulates WRN helicase unwinding of RNA-containing Okazaki fragment-like hybrids and RNA-containing 'chicken-foot' structures in vitro, suggesting cooperative function at replication forks; WRN preferentially unwinds RNA-containing substrates while DHX9 alone fails to unwind Okazaki fragment-like hybrids. In vitro helicase unwinding assay with synthetic RNA-containing substrates; stimulation experiments with purified DHX9 Nucleic acids research Medium 20385589
2010 WRN exonuclease activity is blocked by 3′ obstructive groups (3′-phosphate, 3′-phosphoglycolate, 3′-tyrosyl); WRN degrades 3′-OH substrates non-processively but cannot excise any of these common oxidative damage termini. In vitro exonuclease activity assay on substrates with defined 3′ blocking lesions; side-by-side comparison with APE1, TREX1, p53 Mechanisms of ageing and development Medium 17224176
2010 Acetylation of WRN at 6 specific lysine residues (by CBP/p300) stabilizes WRN protein by inhibiting ubiquitination; SIRT1 deacetylation reverses this stabilization; CBP dramatically increases WRN half-life in a manner abolished by the 6KR (lysine-to-arginine) acetylation-site mutant; WRN is strongly acetylated and stabilized after MMC treatment. Identification of acetylation sites; 6KR mutant stability assay; ubiquitination assay; half-life measurement with cycloheximide chase; MMC treatment acetylation assay; cell survival of 6KR mutant cells PloS one High 20428248
2011 XPG interacts directly with WRN through their C-terminal domains and co-localizes with WRN in S-phase nuclear foci at stalled replication forks; the XPG C-terminal domain strongly stimulates WRN helicase activity; XPG itself possesses intrinsic strand annealing activity that cooperates with WRN annealing activity. Co-immunoprecipitation; domain-mapping with C-terminal deletion mutants; in vitro helicase stimulation assay; in vitro strand annealing assay; immunofluorescence co-localization Cell cycle (Georgetown, Tex.) High 21558802
2014 WRN acts epistatically with DNA2 to promote long-range 5′-to-3′ DNA end resection at DSBs in human cells; WRN and DNA2 interact physically and coordinate enzymatic activities to mediate 5′-to-3′ resection in vitro in an RPA-dependent manner; CDK1-mediated phosphorylation of WRN at S1133 is required for interaction with the MRE11 complex to promote DNA2-dependent resection. Epistasis analysis by siRNA co-depletion (resection assay); co-immunoprecipitation of WRN-DNA2; in vitro resection assay with purified proteins; DNA fiber analysis The Journal of biological chemistry High 25122754
2014 WRN has a nonenzymatic function in preserving nascent DNA strands at replication-associated DSBs: the NBS1 FHA domain recruits WRN to replication-associated DSBs where WRN stabilizes RAD51 and limits MRE11 exonuclease activity on nascent strands, independent of WRN's own catalytic activities. DNA fiber assay for nascent strand length; NBS1-FHA domain interaction mapping; RAD51 focus formation assay; MRE11 inhibitor epistasis; WRN catalytic mutant analysis Cell reports High 25456133
2014 TRF2 specifically stimulates WRN-mediated strand exchange between telomeric substrates (but not non-telomeric substrates); TRF2 basic domain is critical for this stimulation; TRF1 (with similar telomeric DNA binding affinity) has minimal effect; TRF2 is displaced from telomeric DNA by WRN independently of WRN ATPase/helicase activities. In vitro strand exchange assay with telomeric substrates; domain mutant analysis (TRF2 basic domain); comparison with TRF1; ATPase/helicase mutant WRN controls Nucleic acids research High 24880691
2015 The WRN exonuclease domain protects nascent strands from MRE11/EXO1-dependent degradation at perturbed replication forks: loss of WRN exonuclease enhances nascent strand degradation by MRE11/EXO1 downstream of RAD51, while loss of WRN helicase reduces exonucleolytic processing and causes genome instability. DNA fiber assay for nascent strand degradation; WRN exonuclease-specific and helicase-specific mutant analysis in cells; MRE11/EXO1 inhibitor epistasis; RAD51 epistasis Nucleic acids research High 26275776
2016 WRN regulates pathway choice between classical NHEJ and alternative NHEJ at DSBs: WRN promotes c-NHEJ via its helicase and exonuclease activities; WRN inhibits alt-NHEJ using non-enzymatic functions by suppressing MRE11/CtIP recruitment and protecting DSBs from 5′ end resection; WRN knockdown combined with TRF2 depletion increases telomere fusions abrogated by CtIP knockdown. WRN knockdown + enzymatic mutant complementation; end resection assay; MRE11/CtIP recruitment assay at DSBs; telomere fusion assay in mouse embryonic fibroblasts with double knockdown Nature communications High 27922005
2016 CDK1 phosphorylates WRN at serine S1133 at collapsed replication forks; S1133 phosphorylation is required for WRN interaction with the MRE11 complex (but not for WRN focus formation); loss of S1133 phosphorylation prevents DNA2-dependent long-range resection, impairs HR and replication recovery, and licenses NHEJ at collapsed forks in a dominant-negative manner. In vitro CDK1 kinase assay; phospho-specific antibody; S1133A/D phosphomimetic mutant cells; MRE11 co-IP; DNA fiber and resection assays Nature communications High 27634057
2016 ATR-mediated phosphorylation of WRN at serine S1141 leads to ubiquitination and proteasomal degradation of WRN; this dynamic interaction regulates WRN's association with perturbed replication forks, suppresses new origin firing, and is critical for RAD51-dependent DSB repair and prevention of chromosome breakage during replication stress. In vivo S1141 phosphorylation identification; phosphomimetic/phospho-dead mutant analysis; ubiquitination assay; DNA fiber analysis for origin firing; RAD51 focus assay Oncotarget High 26695548
2017 WRN helicase reciprocates along the same ssDNA strand during DNA unwinding (rather than dissociating and rebinding or strand-switching), with limited processivity; this reciprocating mechanism was shown on forked, overhanging, and G-quadruplex-containing DNA substrates. Single-molecule FRET (smFRET) analysis of WRN unwinding mechanism on defined substrates Scientific reports Medium 28266653
2018 Multiple RPA molecules convert WRN from a weak, repetitive (few-tens-of-bp) helicase into a 'superhelicase' capable of unidirectional unwinding of >1 kb dsDNA; single-molecule FRET and magnetic tweezers demonstrate that binding of multiple RPAs to WRN fundamentally alters its activity and processivity. Single-molecule FRET; magnetic tweezers; titration of RPA molecules on WRN helicase activity Nucleic acids research High 29668972
2018 HERC2 facilitates RPA association with BLM and WRN helicase complexes through HERC2's HECT E3 ubiquitin ligase activity that ubiquitinates RPA2, enabling RPA release onto ssDNA; HERC2 depletion dissociates RPA from WRN/BLM complexes and increases G-quadruplex DNA formation; epistasis analysis shows HERC2 acts through BLM and WRN for G4 suppression. Co-immunoprecipitation; CRISPR/Cas9 deletion of HERC2 E3 catalytic site; RPA2 ubiquitination assay; G4 staining; siRNA epistasis (triple depletion); in vitro RPA release assay Cancer research High 30279242
2018 MDM2 acts as an E3 ubiquitin ligase for WRN: MDM2 interacts with WRN in vivo and in vitro, induces WRN ubiquitination and degradation; DNA damage causes WRN translocation to the nucleoplasm followed by MDM2-mediated degradation; MDM2-dependent WRN degradation mediates cellular senescence in a p53-independent manner. Co-immunoprecipitation in vivo and in vitro; ubiquitination assay; WRN protein stability assay; senescence assay with etoposide; ectopic WRN rescue experiment Oncogene High 30532073
2019 PARP1 protein (but not its enzymatic activity) is required for H2O2- and CEES-induced nucleolar-to-nucleoplasmic translocation of WRN in HeLa cells; CPT-induced WRN translocation is independent of PARP1 protein; gossypol (which disrupts PARP1 protein interactions) abolishes WRN translocation, indicating PARP1-protein interactions mediate this stress-specific shuttling. Immunofluorescence tracking of WRN nucleolar-nucleoplasmic shuttling; PARP1 siRNA knockdown; PARP enzymatic inhibitors vs. gossypol; comparison across multiple genotoxins Scientific reports Medium 31296950
2019 WRN helicase activity (but not exonuclease activity) is selectively essential in MSI cancer models in vitro and in vivo; WRN depletion in MSI cells induces DSBs, apoptosis, and cell cycle arrest, but not in microsatellite-stable cells. CRISPR-Cas9 knockout and RNAi screens; helicase-dead vs. exonuclease-dead WRN complementation; in vivo xenograft models; γ-H2AX/apoptosis/cell cycle readouts Nature High 30971823
2020 Expanded TA-dinucleotide repeats in MSI cells form non-B DNA secondary structures that stall replication forks, activate ATR, and require unwinding by WRN helicase; in the absence of WRN, expanded TA repeats are cleaved by MUS81 nuclease, causing massive chromosome shattering. DNA fiber assay for replication fork stalling; ATR activation assay; TA-repeat expansion measurement in MSI cells; MUS81 epistasis (knockout); WRN depletion in isogenic MSI/MSS cells; cytogenetic analysis of chromosome shattering Nature High 32999459
2021 WRN helicase ensures efficient restart and limits excessive degradation of stalled replication forks in BRCA2-deficient cancer cells; in vitro, WRN ATPase/helicase restores regressed forks and curtails MRE11 nuclease activity on regressed fork substrates; WRN helicase inhibition traps WRN on chromatin leading to fork stalling, MRE11-dependent nucleolytic degradation, MUS81-dependent DSBs, and elevated NHEJ. In vitro fork restoration/regression assay with purified WRN; WRN helicase inhibitor treatment in BRCA2-deficient cells; DNA fiber assay; MRE11/MUS81 epistasis; BRCA2-deficient xenograft tumor model Nature communications High 34772932
2021 WRN phosphorylation by CDK2 at serine 426 is critical for DSB repair pathway choice: S426 phosphorylation stabilizes WRN's affinity for RPA and promotes long-range resection required for HR; unphosphorylated WRN shows altered DSB recruitment, reduced RPA interaction, and altered strand annealing and DSB repair activities. In vitro CDK2 kinase assay; phosphomimetic/phospho-dead S426 mutant cells; RPA co-immunoprecipitation; strand annealing assay; DSB repair pathway assay; laser-induced DSB recruitment Aging cell High 34612580
2022 WRN helicase directly unfolds cruciform DNA structures in vitro, preventing cleavage by SLX1-SLX4 structure-specific endonuclease; TA-repeat sequences are particularly prone to form cruciforms; WRN and MMR complex MutLα exhibit synergistic (higher-than-additive) cruciform processing in vitro, suggesting cooperative function. In vitro cruciform DNA unwinding/processing assay; SLX1-SLX4 cleavage assay; TA-repeat cruciform formation assay; combined WRN + MutLα assay The EMBO journal High 36541070
2022 WRN helicase domain regulates transcriptional expression of SHOX by unwinding G-quadruplex structures in the SHOX promoter region; WRN-null zebrafish exhibit impaired bone growth rescued by SHOX/shox overexpression; chondrogenesis requires WRN and is linked specifically to its helicase domain. WRN/wrn knockout zebrafish model; SHOX identification as WRN target; G-quadruplex unwinding assay; genetic rescue with SHOX overexpression in WRN-null background; in vitro transcription/promoter assay Nature communications High 36114168
2024 HRO761, an allosteric WRN helicase inhibitor, binds at the interface of the D1 and D2 helicase domains of WRN, locking it in an inactive conformation; pharmacological inhibition recapitulates WRN-depletion phenotype (DNA damage, selective MSI cell growth inhibition); HRO761 causes WRN degradation in MSI but not MSS cells. X-ray/cryo structural characterization of HRO761-WRN complex; biochemical helicase inhibition assay; selectivity profiling; cellular DNA damage assay; WRN protein stability assay in MSI vs. MSS cells; in vivo xenograft Nature High 38658754
2024 VVD-133214, a covalent allosteric WRN inhibitor, selectively engages cysteine C727 in the helicase domain at a region subject to interdomain movement during DNA unwinding; binding is cooperative with nucleotide and stabilizes compact conformations lacking dynamic flexibility for helicase function, causing DSBs and cell death selectively in MSI-H cells. Chemoproteomics identification of C727; covalent binding characterization; nucleotide cooperativity assay; conformational studies; selective cellular toxicity in MSI-H vs. MSS cells; in vivo xenograft models Nature High 38658751
2025 WRN (with DNA2) specifically resects the 5′ end of ssDNA gaps through a mechanism distinct from DSB end resection, independent of MRN-CtIP; this 5′-gap resection by DNA2-WRN/BLM alters ssDNA gap repair kinetics and, in BRCA1-deficient cells, excessive resection leads to larger gaps causing DNA breaks in subsequent cell cycles. Single-molecule DNA fiber analysis; electron microscopy; biochemical resection assays with purified proteins; epistasis with MRN-CtIP knockdown; BRCA1-deficient cell analysis Genes & development High 40127955

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature 348 30971823
2000 Werner's syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest. EMBO reports 329 11256630
2001 SGS1, the Saccharomyces cerevisiae homologue of BLM and WRN, suppresses genome instability and homeologous recombination. Nature genetics 284 11138010
1999 Functional and physical interaction between WRN helicase and human replication protein A. The Journal of biological chemistry 265 10373438
2014 DNA2 cooperates with the WRN and BLM RecQ helicases to mediate long-range DNA end resection in human cells. The Journal of biological chemistry 180 25122754
2006 The spectrum of WRN mutations in Werner syndrome patients. Human mutation 167 16673358
2020 Repeat expansions confer WRN dependence in microsatellite-unstable cancers. Nature 159 32999459
2005 POT1 stimulates RecQ helicases WRN and BLM to unwind telomeric DNA substrates. The Journal of biological chemistry 157 16030011
2000 Mutations in the WRN gene in mice accelerate mortality in a p53-null background. Molecular and cellular biology 151 10757812
2008 Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation. The Journal of biological chemistry 145 18203716
2010 ATR and ATM differently regulate WRN to prevent DSBs at stalled replication forks and promote replication fork recovery. The EMBO journal 139 20802463
2006 WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing. Nature structural & molecular biology 131 16622405
2008 Up-regulation of WRN and DNA ligase IIIalpha in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaks. Blood 128 18524993
2003 WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repair. Aging cell 118 12934712
2005 The Pso4 mRNA splicing and DNA repair complex interacts with WRN for processing of DNA interstrand cross-links. The Journal of biological chemistry 112 16223718
2004 TRF2 recruits the Werner syndrome (WRN) exonuclease for processing of telomeric DNA. Oncogene 104 14712220
2003 WRN interacts physically and functionally with the recombination mediator protein RAD52. The Journal of biological chemistry 104 12750383
2016 WRN regulates pathway choice between classical and alternative non-homologous end joining. Nature communications 93 27922005
2002 The Werner syndrome helicase/exonuclease (WRN) disrupts and degrades D-loops in vitro. Biochemistry 90 12427008
2024 Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers. Nature 89 38658754
2024 Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase. Nature 83 38658751
2016 WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects. Human mutation 83 27667302
2007 WRN at telomeres: implications for aging and cancer. Journal of cell science 75 17314245
2000 WRN helicase expression in Werner syndrome cell lines. Nucleic acids research 74 10606667
2004 Regulation of WRN helicase activity in human base excision repair. The Journal of biological chemistry 71 15385537
2015 The WRN exonuclease domain protects nascent strands from pathological MRE11/EXO1-dependent degradation. Nucleic acids research 70 26275776
2009 c-Myc accelerates S-phase and requires WRN to avoid replication stress. PloS one 70 19554081
2002 WRN helicase accelerates the transcription of ribosomal RNA as a component of an RNA polymerase I-associated complex. Oncogene 70 11971179
1999 WRN mutations in Werner syndrome. Human mutation 70 10220139
2014 Nonenzymatic role for WRN in preserving nascent DNA strands after replication stress. Cell reports 67 25456133
2010 The human WRN and BLM RecQ helicases differentially regulate cell proliferation and survival after chemotherapeutic DNA damage. Cancer research 67 20663905
2002 Biochemical characterization of the WRN-FEN-1 functional interaction. Biochemistry 62 12356323
2014 Structural mechanisms of human RecQ helicases WRN and BLM. Frontiers in genetics 61 25400656
2008 WRN controls formation of extrachromosomal telomeric circles and is required for TRF2DeltaB-mediated telomere shortening. Molecular and cellular biology 60 18212065
2011 RECQL1 and WRN proteins are potential therapeutic targets in head and neck squamous cell carcinoma. Cancer research 58 21571861
2003 Telomere instability in a human tumor cell line expressing a dominant-negative WRN protein. Human genetics 58 12827497
2016 Bloom's syndrome: Why not premature aging?: A comparison of the BLM and WRN helicases. Ageing research reviews 56 27238185
2008 WRN is required for ATM activation and the S-phase checkpoint in response to interstrand cross-link-induced DNA double-strand breaks. Molecular biology of the cell 56 18596239
2016 CDK1 phosphorylates WRN at collapsed replication forks. Nature communications 55 27634057
2005 The interaction site of Flap Endonuclease-1 with WRN helicase suggests a coordination of WRN and PCNA. Nucleic acids research 55 16326861
2007 Replication fork regression in vitro by the Werner syndrome protein (WRN): holliday junction formation, the effect of leading arm structure and a potential role for WRN exonuclease activity. Nucleic acids research 52 17717003
2018 HERC2 Facilitates BLM and WRN Helicase Complex Interaction with RPA to Suppress G-Quadruplex DNA. Cancer research 51 30279242
2010 Acetylation of WRN protein regulates its stability by inhibiting ubiquitination. PloS one 49 20428248
2010 BCR/ABL stimulates WRN to promote survival and genomic instability. Cancer research 47 21123451
2010 WRN helicase unwinds Okazaki fragment-like hybrids in a reaction stimulated by the human DHX9 helicase. Nucleic acids research 46 20385589
2005 p53 modulates RPA-dependent and RPA-independent WRN helicase activity. Cancer research 46 15735006
2005 Cellular dynamics and modulation of WRN protein is DNA damage specific. Mechanisms of ageing and development 46 16087220
2012 MYC-driven tumorigenesis is inhibited by WRN syndrome gene deficiency. Molecular cancer research : MCR 44 22301954
2021 WRN helicase safeguards deprotected replication forks in BRCA2-mutated cancer cells. Nature communications 42 34772932
2012 The WRN and MUS81 proteins limit cell death and genome instability following oncogene activation. Oncogene 42 22410776
2011 The DNA repair endonuclease XPG interacts directly and functionally with the WRN helicase defective in Werner syndrome. Cell cycle (Georgetown, Tex.) 42 21558802
2024 Novel WRN Helicase Inhibitors Selectively Target Microsatellite-Unstable Cancer Cells. Cancer discovery 41 38587317
2019 A high-throughput screen to identify novel small molecule inhibitors of the Werner Syndrome Helicase-Nuclease (WRN). PloS one 41 30625228
2011 WRN helicase regulates the ATR-CHK1-induced S-phase checkpoint pathway in response to topoisomerase-I-DNA covalent complexes. Journal of cell science 41 22159421
2018 Nonfunctional mutant Wrn protein leads to neurological deficits, neuronal stress, microglial alteration, and immune imbalance in a mouse model of Werner syndrome. Brain, behavior, and immunity 39 29908963
2017 Werner syndrome (WRN) gene variants and their association with altered function and age-associated diseases. Ageing research reviews 39 29146545
2012 The roles of WRN and BLM RecQ helicases in the Alternative Lengthening of Telomeres. Nucleic acids research 39 22989712
2004 The Werner syndrome protein confers resistance to the DNA lesions N3-methyladenine and O6-methylguanine: implications for WRN function. DNA repair 38 15135730
2014 Rapamycin decreases DNA damage accumulation and enhances cell growth of WRN-deficient human fibroblasts. Aging cell 37 24308646
2006 Werner syndrome and mutations of the WRN and LMNA genes in France. Human mutation 37 16786514
2011 Proteome-wide identification of WRN-interacting proteins in untreated and nuclease-treated samples. Journal of proteome research 36 21210717
2007 Genetic variation in the premature aging gene WRN: a case-control study on breast cancer susceptibility. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 36 17301258
2016 Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer. Oncotarget 35 26959889
2018 Multiple RPAs make WRN syndrome protein a superhelicase. Nucleic acids research 34 29668972
2019 PARP1 regulates DNA damage-induced nucleolar-nucleoplasmic shuttling of WRN and XRCC1 in a toxicant and protein-specific manner. Scientific reports 32 31296950
2017 Single-molecule studies reveal reciprocating of WRN helicase core along ssDNA during DNA unwinding. Scientific reports 32 28266653
2006 Analyses of the interaction of WRNIP1 with Werner syndrome protein (WRN) in vitro and in the cell. DNA repair 32 16769258
2022 WRN helicase and mismatch repair complexes independently and synergistically disrupt cruciform DNA structures. The EMBO journal 31 36541070
2008 Acetylation regulates WRN catalytic activities and affects base excision DNA repair. PloS one 31 18398454
2015 RECQL1 and WRN DNA repair helicases: potential therapeutic targets and proliferative markers against cancers. Frontiers in genetics 30 25620975
2011 Non-B DNA-forming sequences and WRN deficiency independently increase the frequency of base substitution in human cells. The Journal of biological chemistry 30 21285356
2009 Colorectal cancer and polymorphisms in DNA repair genes WRN, RMI1 and BLM. Carcinogenesis 30 19945966
2006 WRN exonuclease activity is blocked by DNA termini harboring 3' obstructive groups. Mechanisms of ageing and development 30 17224176
2006 Enzymatic mechanism of the WRN helicase/nuclease. Methods in enzymology 28 16793395
2021 The WRN helicase: resolving a new target in microsatellite unstable cancers. Current opinion in genetics & development 27 34284257
2018 MDM2-mediated degradation of WRN promotes cellular senescence in a p53-independent manner. Oncogene 27 30532073
2016 Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway. Oncotarget 27 26695548
2010 Cooperation of DNA-PKcs and WRN helicase in the maintenance of telomeric D-loops. Aging 27 20519774
2006 The role of WRN in DNA repair is affected by post-translational modifications. Mechanisms of ageing and development 27 17116323
2008 Intrinsic ssDNA annealing activity in the C-terminal region of WRN. Biochemistry 26 18771289
2023 Identification of 2-Sulfonyl/Sulfonamide Pyrimidines as Covalent Inhibitors of WRN Using a Multiplexed High-Throughput Screening Assay. Biochemistry 25 37403936
2014 WRN loss induces switching of telomerase-independent mechanisms of telomere elongation. PloS one 25 24709898
2010 WRN participates in translesion synthesis pathway through interaction with NBS1. Mechanisms of ageing and development 25 20600238
2022 R-Loop-Associated Genomic Instability and Implication of WRN and WRNIP1. International journal of molecular sciences 24 35163467
2021 Pharmacological targeting of differential DNA repair, radio-sensitizes WRN-deficient cancer cells in vitro and in vivo. Biochemical pharmacology 24 33571504
2022 Clinical prospects of WRN inhibition as a treatment for MSI tumours. NPJ precision oncology 23 36379964
2016 WRN-targeted therapy using inhibitors NSC 19630 and NSC 617145 induce apoptosis in HTLV-1-transformed adult T-cell leukemia cells. Journal of hematology & oncology 23 27829440
2013 Polymorphisms of the WRN gene and DNA damage of peripheral lymphocytes in age-related cataract in a Han Chinese population. Age (Dordrecht, Netherlands) 23 23334603
2012 RECQL5 plays co-operative and complementary roles with WRN syndrome helicase. Nucleic acids research 23 23180761
2024 Challenges for the Discovery of Non-Covalent WRN Helicase Inhibitors. ChemMedChem 22 38334957
2014 The FEN1 E359K germline mutation disrupts the FEN1-WRN interaction and FEN1 GEN activity, causing aneuploidy-associated cancers. Oncogene 22 24608430
2014 Strand exchange of telomeric DNA catalyzed by the Werner syndrome protein (WRN) is specifically stimulated by TRF2. Nucleic acids research 22 24880691
2008 WRN protects against topo I but not topo II inhibitors by preventing DNA break formation. DNA repair 22 18805512
2020 WRN-Mutated Colorectal Cancer Is Characterized by a Distinct Genetic Phenotype. Cancers 21 32455893
2015 Metabolic and Phenotypic Differences between Mice Producing a Werner Syndrome Helicase Mutant Protein and Wrn Null Mice. PloS one 21 26447695
2022 WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome. Nature communications 20 36114168
2021 CDK2 phosphorylation of Werner protein (WRN) contributes to WRN's DNA double-strand break repair pathway choice. Aging cell 20 34612580
2008 Werner syndrome protein, WRN, protects cells from DNA damage induced by the benzene metabolite hydroquinone. Toxicological sciences : an official journal of the Society of Toxicology 20 19064679
2007 WRN counteracts the NHEJ pathway upon camptothecin exposure. Biochemical and biophysical research communications 20 17303082
2025 MRN-CtIP, EXO1, and DNA2-WRN/BLM act bidirectionally to process DNA gaps in PARPi-treated cells without strand cleavage. Genes & development 19 40127955

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