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FLASH GENE
Symbol WRN contributors: mct/ - updated : 09-02-2011
HGNC name Werner syndrome, RecQ helicase-like
HGNC id 12791
Corresponding disease
WRN Werner syndrome
Location 8p12      Physical location : 30.890.777 - 31.031.276
Synonym name
  • Werner syndrome helicase
  • DNA helicase, RecQ-like type 3
  • Synonym symbol(s) RECQL2, RECQ3, DKFZp686C2056, RECQL3
    EC.number 3.6.4.12
    DNA
    TYPE functioning gene
    STRUCTURE 140.50 kb     35 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked Y status confirmed
    Physical map
    EXTL3 8p21 exostoses (multiple)-like 3 FLJ10871 8p21.1 hypothetical protein FLJ10871 FLJ21616 8p21.1 hypothetical protein FLJ21616 KIF13B 8p21-p12 kinesin family member 13B DUSP4 8p12-p11 dual specificity phosphatase 4 LOC392208 8 similar to Ac2-210 LOC389645 8 LOC389645 MAP2K1P1 8p21 mitogen-activated protein kinase kinase 1 pseudogene 1 MGC8721 8p12 hypothetical protein MGC8721 LEPROTL1 8p21.2-p21.1 leptin receptor overlapping transcript-like 1 DCTN6 8p12-p11 dynactin 6 LOC392209 8 similar to heat shock protein (hsp-2) LOC92755 8p21.1 hypothetical gene LOC92755 RBPMS 8p12-p11 RNA binding protein with multiple splicing GTF2E2 8p12-p11 general transcription factor IIE, polypeptide 2, beta 34kDa GSR 8p21.1 glutathione reductase D8S2298E 8p12-p11.2 Homo sapiens reproduction 8 (D8S2298E), mRNA. PPP2CB 8p12-p11.2 protein phosphatase 2 (formerly 2A), catalytic subunit, beta isoform TEX15 8p12 testis expressed sequence 15 PURG 8p11 purine-rich element binding protein G WRN 8p12-p11.2 Werner syndrome LOC157589 8p12 similar to potassium channel tetramerisation domain containing 9 NRG1 8p21-p12 neuregulin 1 FUT10 8p12 fucosyltransferase 10 (alpha (1,3) fucosyltransferase)
    RNA
    TRANSCRIPTS type messenger
    text two transcription initiation sites
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    35 - 5765 - 1432 - 2008 18852298
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Hearing/Equilibriumear   highly
    Respiratoryrespiratory tractlarynx  highly
    Urinarybladder   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadipose  highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    cell cycle     cell cycle, checkpoint, G2M
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N-terminal 3' to 5' exonuclease domain
  • an acidic region
  • seven RecQ helicase domains including an ATPase domain
  • a RecQ helicase conserved domain (RQC), major site of interaction for DNA and proteins, crucial for WRN helicase and its coordinated functions
  • a helicase, RnaseD, C-terminal conserved region (HRDC)
  • a nuclear localization signal (NLS) in the large C terminal domain
  • two RPA binding sites, a high affinity N-terminal site, and a lower affinity C-terminal site
  • mono polymer dimer , tetramer
    HOMOLOGY
    interspecies homolog to yeast Sgs1
    homolog to C.elegans F18C5.2
    homolog to X laevis focus forming activity 1 (FFA1)
    homolog to E.coli RecQ
    Homologene
    FAMILY
  • helicase family
  • RecQ subfamily
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,nucleolus
    text efficiently relocalized in nuclear foci in replicating cells
    basic FUNCTION
  • multifunctional nuclear protein possessing 3'-5' exonuclease and ATP-dependent helicase activities
  • contributes to the maintenance of genome integrity through its involvement in DNA repair
  • plays a direct role in the repair of methylation-induced DNA damage
  • involved in genome stability maintenance and in preventing aberrant deleterious recombinogenic pathways when replication perturbed by DNA damage, alternate DNA structure or impaired DNA synthesis
  • involved in 3' to 5' DNA ATP dependent, unwinding function, in RNA polymerase II activation in DNA repair replication foci formation through interaction with POLDs
  • involved with PRKDC in non-homologous end joining
  • involved in telomere dynamics and maintenance
  • facilitating FEN1 cleavage of DNA replication/repair intermediates, important for the role of WRN in the maintenance of genomic stability
  • possessing a 3' to 5' exonuclease activity in addition to the 3' to 5' helicase activity characteristic of other RecQ proteins
  • required for genomic stability and avoidance of cancer
  • having ATPase, helicase, exonuclease and single-stranded DNA annealing activities
  • may protect the genome from the lethal, mutagenic and carcinogenic effects of widely diverse DNA damage arising from endogenous processes and environmental agents
  • playing roles in dissociating telomeric structures in telomerase-deficient cells
  • playing a role in processing of telomeric DNA and subsequent activation of DNA damage responses
  • having an helicase activity necessary to prevent dramatic telomere loss during DNA replication
  • playing a role in homology-dependent recombination repair (HDR) that can be used to repair DNA damage while suppressing gene loss or rearrangement
  • also has an important role in the maintenance of telomere length and the suppression of telomere sister-chromatid exchanges
  • functioning in dissociating alternative DNA structures during recombination and/or replication at telomeric ends
  • plays a significant role in oxidative DNA damage repair via an important association with NEIL1
  • undergoing metal-catalyzed oxidation in the presence of iron (iron-mediated oxidation of WRN likely results in the accumulation of a catalytically inactive form of the protein, which may contribute to age-related phenotypes, and oxidatively modified WRN may have deleterious effects on DNA repair and telomere maintenance pathways)
  • might regress replication forks as part of a genome maintenance pathway
  • may prevent the stalling and collapse of replication forks that encounter damaged DNA
  • required to avoid accumulation of double-strand breaks and fork collapse after replication perturbation
  • contributes to the maintenance of genomic integrity through its involvement in DNA repair, replication and recombination
  • participates in the same repair pathway as NEIL1
  • key regulator of fragile site stability
  • stabilizes fragile sites acting in a common pathway with the ataxia telangiectasia and Rad3 related replication checkpoint (providing the first evidence of a crucial role for a helicase in protecting cells against chromosome breakage at normally occurring replication fork stalling sites)
  • cooperation between both helicases WRN and DHX9, may serve to form and to dissolve Holliday junction-like intermediates of regressed replication forks
  • may be playing a role in Okazaki fragment maturation
  • cooperative functions for WRN and DHX9 at both migrating and stalled replication forks, where they seem to be involved in the removal of primer RNA-containing Okazaki fragments
  • directly phosphorylated by ATR at multiple C-terminal S/TQ residues
  • with POT1, are required for efficient chromosome segregation
  • WRN and BLM are critical for maintaining genomic stability and thought to function in accurate resolution of replication blockage
  • WRN and POLD1, are involved in maintaining cellular genomic stability
  • CELLULAR PROCESS nucleotide, replication
    nucleotide, recombination
    nucleotide, repair
    nucleotide, genomic integrity
    PHYSIOLOGICAL PROCESS
    text resolving aberrant structures that arise from DNA replication, recombination and/or repair
    PATHWAY
    metabolism
    signaling
    chromosome instability pathway
    a component
  • with FEN1 upon replication arrest
  • in solution, WRN exists predominantly as a dimer
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • TP53
  • POL2 and recruiting it to the nucleolus
  • 5'flap endonuclease (FEN1) cleavage activity, important in DNA metabolism and consistent with a role of the conserved non-catalytic domain of RecQ helicase in DNA replication intermediate processing
  • interacting with BLM
  • telomerase and TRF2
  • PRKDC
  • stimulating cleavage activity of FEN1
  • interaction with RPA or BLM helicases plays an important role in the mechanism for RPA stimulation of helicase-catalyzed DNA unwinding
  • associates with NEIL1 in the early damage-sensing step of base excision repair (participates in the same repair pathway as NEIL1)
  • physically interacts with the MSH2/MSH6, MSH2/MSH3 and MLH1/PMS2
  • binds at the junction of a replication fork and at Holliday junction structures
  • interacting with NEIL1 (associates with NEIL1 in the early damage-sensing step of base excision repair, stimulating NEIL1 in excision of oxidative lesions from bubble DNA substrates)
  • interacting with TERF2 (can protect telomeric HJs (Holliday junctions) from WRN activity only if both TERF2 DNA-binding domains simultaneously engage the HJ core and the arms)
  • physically interacts with the major NHEJ (Nonhomologous end-joining) factor, XRCC4-DNA ligase IV complex, which stimulates WRN exonuclease but not its helicase activity
  • upon replication blockage, WRN and RPA1 functionally interact and cooperate to help properly resolve replication forks and maintain genome stability
  • ERCC5 interacts directly with WRN, which is defective in the premature aging disorder Werner syndrome, and the two proteins undergo similar subnuclear redistribution in S phase and colocalize in nuclear foci
  • SUPV3L1 interact with BLM and WRN, members of the RecQ helicase family involved in multiple DNA metabolic processes, and in protection and stabilization of the genome
  • ERCC5 interacts directly and functionally with the WRN helicase (stimulates the helicase activity of WRN, and XPG and WRN work cooperatively to anneal two DNA single strands)
  • RECQL4 and WRN are present in the same complex and, although RECQL4 by itself has very little activity on telomeric D-loops, it can work synergistically with WRN and resolve telomeric D-loops very efficiently
  • importance of WRN exonuclease activity and its cooperativity with POLD1 in preserving genome stability, which is compromised by the loss of WRN in Werner syndrome
  • cell & other
    REGULATION
    activated by Ku heterodimer (KUP70/KUP80)
    replication proteins RPA1,RPA2,RPA3
    upregulated at the G2/M stage of the cell cycle
    inhibited by PRKDC
    phosphorylated through an ATR/ATM dependent payhway following replication arrest and DNA damage induced during S phase of the cell cycle
    APEX1
    Other modulated by its post-translational modifications in response to DNA damage
    regulated by ATM (ATM-dependent regulation of WRN de-localisation from replication fork stalling sites contribute to ensure cellular recovery after DSB formation at stalled forks)
    phosphorylation of WRN has a vital function in the S-phase checkpoint response, promoting the failsafe recovery from replication arrest and the engagement of recombination upon fork collapse
    ASSOCIATED DISORDERS
    corresponding disease(s) WRN
    related resource Werner Syndrome mutation database
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral somatic mutation      
    missense mutations or polymorphisms could promote genetic instability and cancer by selectively interfering with recombination in somatic cells
    tumoral     --low  
    deficiency is associated with accumulation of gaps and breaks at common fragile sites even under unperturbed conditions
    Susceptibility
  • to age related disorders such as atherosclerosis
  • to enhanced longevity
  • Variant & Polymorphism SNP L1074F, C1367R
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerhead and neck 
    RECQL and WRN proteins are potential therapeutic targets in head and neck squamous cell carcinoma
    ANIMAL & CELL MODELS