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FLASH GENE

Symbol

WRN

contributors: mct/ - updated : 23-08-2019

HGNC name	Werner syndrome, RecQ helicase-like
HGNC id	12791

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

RNA

TRANSCRIPTS	type	messenger

text	two transcription initiation sites

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000553 35 - 5765 NP_000544 - 1432 - 2008 18852298

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Hearing/Equilibrium ear       highly Respiratory respiratory tract larynx     highly Urinary bladder       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose     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, shown to regulate its transcriptional activity, and that affects the transcription of certain proteins involved in autophagy and aging
	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, and necessary for full stimulation of POLN activity , RecQ-C-terminal (RQC) domain of WRN imparting a 2-fold preference for binding to G4 DNA relative to non-G4 DNA substrates
	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,cytoplasm,cytoskeleton,microtubule,centrosome
	intracellular,nucleus,nucleoplasm,nuclear bodies,nuclear speckles
	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
	is necessary to sustain replication fork progression in response to oncogene-induced replication stress
	is involved in (CTG)n hairpin removal by resolving the hairpin, promoting DNA synthesis
	plays an important role in maintaining TNR
	(trinucleotide repeat) stability during DNA replication and repair by resolving CTG hairpins
	exonuclease activity of WRN prevents stable mispair formation by POLN (PMID;:
	RECQL may participate in the same pathway as WRN, probably in telomere replication
	WRN may have a role in controlling autophagy and hereby cellular maintenance.
	WRN clearly prefers to act on strand invasion intermediates in a manner that favours strand invasion and exchange
	unique role for WRN as a modulator of DNA repair, replication, and recombination, and link ATR-WRN signaling to the maintenance of genome stability
	WRN RECQ protein as a G4 helicase that modulates gene expression in G4-dependent fashion at many chromosomal sites
	has important connections with non-S-phase-dependent DNA repair events such as NHEJ and excision repair
	regulates the pathway choice between classical (c)- and alternative (alt)-nonhomologous end joining (NHEJ) during DNA double-strand break (DSB) repair

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
	double-strand breaks, observed upon oncogene over-expression, depend on the MUS81 endonuclease, which represents a parallel pathway collaborating with WRN to prevent cell death
	WRN improves the efficiency and fidelity of POLN to promote more effective replication of DNA
	RECQL5 plays both co-operative and complementary roles with WRN
	WRN and BLM act epistatically with DNA2 to promote the long-range resection of double strand break ends in human cells
	WRN and DNA2 interact physically and coordinate their enzymatic activities to mediate 5'-3' DNA end resection in a reaction dependent on RPA1
	is regulated by SIRT1 and increased expression of WRN might be one of the determinants for the development of chemotherapeutic drug resistance
	PARP1 and PAR (PolyADP ribose) actively, and in some instances differentially, regulate the activities and cellular localization of RECQL5 and WRN
	DNA2 motor promotes the enzyme capacity to degrade dsDNA in conjunction with BLM or WRN and thus promote the repair of broken DNA
	WRN participates in one of the two alternative long-range resection pathways mediated by DNA2 or EXO1
	RECQL5 co-operates with WRN on synthetic stalled replication fork-like structures and stimulates its helicase activity on DNA fork duplexes

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

Phosphorylated by

CDK1, and this phosphorylation is essential to perform DNA2-dependent end resection at replication-related DSBs, promoting HR, replication recovery and chromosome stability

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed cancer head and neck   RECQL and WRN proteins are potential therapeutic targets in head and neck squamous cell carcinoma

ANIMAL & CELL MODELS