Werner syndrome helicase

Werner syndrome ATP-dependent helicase, also known as DNA helicase, RecQ-like type 3, is an enzyme that in humans is encoded by the WRN gene. WRN is a member of the RecQ Helicase family.[5] Helicase enzymes generally unwind and separate double-stranded DNA. These activities are necessary before DNA can be copied in preparation for cell division (DNA replication). Helicase enzymes are also critical for making a blueprint of a gene for protein production, a process called transcription. Further evidence suggests that Werner protein plays a critical role in repairing DNA. Overall, this protein helps maintain the structure and integrity of a person's DNA.

WRN
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2AXL, 2DGZ, 2E1E, 2E1F, 2FBT, 2FBV, 2FBX, 2FBY, 2FC0, 3AAF
Identifiers
Aliases	WRN, RECQ3, RECQL2, RECQL3, Werner syndrome RecQ like helicase, WRN RecQ like helicase
External IDs	OMIM: 604611 MGI: 109635 HomoloGene: 6659 GeneCards: WRN
EC number	3.1.-.-
Gene location (Human) Chr. Chromosome 8 (human)[1] Band 8p12 Start 31,033,788 bp[1] End 31,176,138 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8 A3|8 20.3 cM Start 33,234,384 bp[2] End 33,385,527 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • DNA binding • nucleotide binding • manganese ion binding • protein homodimerization activity • GO:0008026 helicase activity • GO:0004003 DNA helicase activity • bubble DNA binding • chromatin binding • metal ion binding • G-quadruplex DNA binding • ATPase activity • GO:0001948 protein binding • catalytic activity • 3'-5' exonuclease activity • Y-form DNA binding • nucleic acid binding • nuclease activity • GO:0043140 3'-5' DNA helicase activity • GO:1990163 four-way junction helicase activity • ATP binding • magnesium ion binding • hydrolase activity • exonuclease activity • telomeric D-loop binding • 3'-flap-structured DNA binding • four-way junction DNA binding • forked DNA-dependent helicase activity • telomeric G-quadruplex DNA binding • 8-hydroxy-2'-deoxyguanosine DNA binding • GO:0032403 macromolecular complex binding • MutLalpha complex binding Cellular component • centrosome • intracellular • nucleoplasm • nucleolus • neuron projection • MutLalpha complex • cell nucleus • cytoplasm • nuclear speck • chromosome, telomeric region • replication fork • DNA replication factor A complex • chromosome • site of double-strand break Biological process • regulation of apoptotic process • positive regulation of hydrolase activity • DNA recombination • cellular response to starvation • DNA metabolic process • aging • response to oxidative stress • replicative cell aging • cellular response to DNA damage stimulus • cell aging • regulation of growth rate • brain development • cell metabolism • cellular response to gamma radiation • replication fork processing • multicellular organism aging • metabolism • nucleobase-containing compound metabolic process • response to UV-C • base-excision repair • double-strand break repair • DNA repair • nucleic acid phosphodiester bond hydrolysis • double-strand break repair via homologous recombination • DNA duplex unwinding • DNA replication • telomeric D-loop disassembly • t-circle formation • positive regulation of strand invasion • telomere maintenance • G-quadruplex DNA unwinding • protein localization to nucleolus • DNA synthesis involved in DNA repair • determination of adult lifespan • regulation of signal transduction by p53 class mediator • DNA unwinding involved in DNA replication Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	7486	22427
Ensembl	ENSG00000165392	ENSMUSG00000031583
UniProt	Q14191	O09053
RefSeq (mRNA)	NM_000553	NM_001122822 NM_011721
RefSeq (protein)	NP_000544	NP_001116294 NP_035851
Location (UCSC)	Chr 8: 31.03 – 31.18 Mb	Chr 8: 33.23 – 33.39 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

The WRN gene is located on the short (p) arm of chromosome 8 between positions 12 and 11.2, from base pair 31,010,319 to base pair 31,150,818.

Structure and function

WRN is a member of the RecQ Helicase family. It is the only RecQ Helicase that contains 3' to 5' exonuclease activity. These exonuclease activities include degradation of recessed 3' ends and initiation of DNA degradation from a gap in dsDNA. WRN is important in repair of double strand breaks by homologous recombination[6][7] or non-homologous end joining,[8] repair of single nucleotide damages by base excision repair,[9][10][5] and is effective in replication arrest recovery.[11] WRN may also be important in telomere maintenance and replication, especially the replication of the G-rich sequences.[12]

WRN is an oligomer that can act as a monomer when unwinding DNA, but as a dimer in solution or a tetramer when complexed with DNA, and has also been observed in tetrameric and hexameric forms. The diffusion of WRN has been measured to 1.62 ${\displaystyle {\tfrac {\mathrm {\mu m} ^{2}}{\mathrm {s} }}}$ in nucleoplasm and 0.12 ${\displaystyle \textstyle {\tfrac {\mathrm {\mu m} ^{2}}{\mathrm {s} }}}$ at nucleoli.[13] Orthologs of WRN have been found in a number of other organisms, including Drosohphila, Xenopus, and C. elegans. WRN is important to genome stability, and cells with mutations to WRN are more susceptible to DNA damage and DNA breaks.[14]

The amino terminus of WRN is involved in both helicase and nuclease activities, while the carboxyl-terminus interacts with p53, an important tumor suppressor.[15] WRN may function as an exonuclease in DNA repair, recombination, or replication, as well as resolution of DNA secondary structures. It is involved in branch migration at Holliday junctions, and it interacts with other DNA replication intermediates.[11] mRNA that codes for WRN has been identified in most human tissues.[15]

Post-translational modification

Phosphorylation of WRN at serine/threonine inhibits helicase and exonuclease activities which are important to post-replication DNA repair. De-phosphorylation at these sites enhances the catalytic activities of WRN. Phosphorylation may affect other post-translational modifications, including sumoylation and acetylation.[12]

Methylation of WRN causes the gene to turn off. This suppresses the production of the WRN protein and its functions in DNA repair.[16]

Clinical significance

Werner syndrome is caused by mutations in the WRN gene.[15] More than 20 mutations in the WRN gene are known to cause Werner syndrome. Many of these mutations result in an abnormally shortened Werner protein. Evidence suggests that the altered protein is not transported into the cell nucleus, where it normally interacts with DNA.[17] This shortened protein may also be broken down too quickly, leading to a loss of Werner protein in the cell. Without normal Werner protein in the nucleus, cells cannot perform the tasks of DNA replication, repair, and transcription.[18] Researchers are still determining how these mutations cause the appearance of premature aging seen in Werner syndrome.

WRN roles in DNA repair pathways

Homologous recombinational repair

WRN is active in homologous recombination. Cells defective in the WRN gene have a 23-fold reduction in spontaneous mitotic recombination, with especial deficiency in conversion-type events.[19] WRN defective cells, when exposed to x-rays, have more chromosome breaks and micronuclei than cells with wild-type WRN.[20] Cells defective in the WRN gene are not more sensitive than wild-type cells to gamma-irradiation, UV light, 4 – 6 cyclobutane pyrimidines, or mitomycin C, but are sensitive to type I and type II topoisomerase inhibitors.[21] These findings suggested that the WRN protein takes part in homologous recombinational repair and in the processing of stalled replication forks.[22]

Non-homologous end joining

WRN has an important role in non-homologous end joining (NHEJ) DNA repair. As shown by Shamanna et al.,[8] WRN is recruited to double-strand breaks (DSBs) and participates in NHEJ with its enzymatic and non-enzymatic functions. At DSBs, in association with Ku (protein), it promotes standard or canonical NHEJ (c-NHEJ), repairing double-strand breaks in DNA with its enzymatic functions and with a fair degree of accuracy. WRN inhibits an alternative form of NHEJ, called alt-NHEJ or microhomology-mediated end joining (MMEJ). MMEJ is an inaccurate mode of repair for double-strand breaks.

Base excision repair

WRN has a role in base excision repair (BER) of DNA. As shown by Das et al.,[9] WRN associates with NEIL1 in the early damage-sensing step of BER. WRN stimulates NEIL1 in excision of oxidative lesions. NEIL1 is a DNA glycosylase that initiates the first step in BER by cleaving bases damaged by reactive oxygen species (ROS) and introducing a DNA strand break via NEIL1's associated lyase activity.[23] NEIL1 recognizes (targets) and removes certain ROS-damaged bases and then incises the abasic site via β,δ elimination, leaving 3′ and 5′ phosphate ends. NEIL1 recognizes oxidized pyrimidines, formamidopyrimidines, thymine residues oxidized at the methyl group, and both stereoisomers of thymine glycol.[24]

WRN also participates in BER through its interaction with Polλ.[10] WRN binds to the catalytic domain of Polλ and specifically stimulates DNA gap filling by Polλ over 8-oxo-G followed by strand displacement synthesis. This allows WRN to promote long-patch DNA repair synthesis by Polλ during MUTYH-initiated repair of 8-oxo-G:A mispairs.

Replication arrest recovery

WRN is also involved in replication arrest recovery. If WRN is defective, replication arrest results in accumulation of DSBs and enhanced chromosome fragmentation.[25] As shown by Pichierri et al.,[25] WRN interacts with the RAD9-RAD1-HUS1 (9.1.1) complex, one of the central factors of the replication checkpoint. This interaction is mediated by the binding of the RAD1 subunit to the N-terminal region of WRN and is instrumental for WRN relocalization to nuclear foci and its phosphorylation in response to replication arrest. (In the absence of DNA damage or replication fork stalling, WRN protein remains localized to the nucleoli.[26]) The interaction of WRN with the 9.1.1 complex results in prevention of DSB formation at stalled replication forks.[25]

WRN deficiencies in cancer

Cells expressing limiting amounts of WRN have elevated mutation frequencies compared with wildtype cells.[27] Increased mutation may give rise to cancer. Patients with Werner Syndrome, with homozygous mutations in the WRN gene, have an increased incidence of cancers, including soft tissue sarcomas, osteosarcoma, thyroid cancer and melanoma.[28]

Mutations in WRN are rare in the general population. The rate of heterozygous loss of-function mutation in WRN is approximately one per million. In a Japanese population the rate is 6 per 1,000, which is higher, but still infrequent.[29]

Mutational defects in the WRN gene are relatively rare in cancer cells compared to the frequency of epigenetic alterations in WRN that reduce WRN expression and could contribute to carcinogenesis. The situation is similar to other DNA repair genes whose expression is reduced in cancers due to mainly epigenetic alterations rather than mutations (see Frequencies of epimutations in DNA repair genes).

The table shows results of analysis of 630 human primary tumors for WRN CpG island hypermethylation.[30] This hypermethylation caused reduced protein expression of WRN, a common event in tumorigenesis.[30]

Frequency of WRN promoter methylation in sporadic cancers

Cancer	Frequency of reduction in cancer[30]
Colorectal cancer	37.9%
Non-small cell lung cancer	37.5%
Gastric cancer	25%
Prostate cancer	20%
Breast cancer	17.2%
Thyroid cancer	12.5%
Non-Hodgkin lymphoma	23.7%
Acute myeloblastic leukemia	4.8%
Chondrosarcomas	33.3%
Osteosarcomas	11.1%

Interactions

Werner syndrome ATP-dependent helicase has been shown to interact with:

• BLM[31]
• DNA-PKcs,[32][33]
• FEN1,[34][35]
• Ku70,[36][37]
• Ku80,[36][37]
• P53,[38][39]
• PCNA,[40][41]
• TERF2,[42] and
• WRNIP1.[43]

References

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2. GRCm38: Ensembl release 89: ENSMUSG00000031583 - Ensembl, May 2017
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22. Sakamoto S, Nishikawa K, Heo SJ, Goto M, Furuichi Y, Shimamoto A (2001). "Werner helicase relocates into nuclear foci in response to DNA damaging agents and co-localizes with RPA and Rad51". Genes Cells. 6 (5): 421–30. doi:10.1046/j.1365-2443.2001.00433.x. PMID 11380620.
23. Jacobs AC, Calkins MJ, Jadhav A, Dorjsuren D, Maloney D, Simeonov A, Jaruga P, Dizdaroglu M, McCullough AK, Lloyd RS (2013). "Inhibition of DNA glycosylases via small molecule purine analogs". PLoS ONE. 8 (12): e81667. doi:10.1371/journal.pone.0081667. PMC 3857224. PMID 24349107.
24. Nemec AA, Wallace SS, Sweasy JB (Oct 2010). "Variant base excision repair proteins: contributors to genomic instability". Seminars in Cancer Biology. 20 (5): 320–8. doi:10.1016/j.semcancer.2010.10.010. PMC 3254599. PMID 20955798.
25. Pichierri P, Nicolai S, Cignolo L, Bignami M, Franchitto A (2012). "The RAD9-RAD1-HUS1 (9.1.1) complex interacts with WRN and is crucial to regulate its response to replication fork stalling". Oncogene. 31 (23): 2809–23. doi:10.1038/onc.2011.468. PMC 3272477. PMID 22002307.
26. Constantinou A, Tarsounas M, Karow JK, Brosh RM, Bohr VA, Hickson ID, West SC (2000). "Werner's syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest". EMBO Rep. 1 (1): 80–4. doi:10.1093/embo-reports/kvd004. PMC 1083680. PMID 11256630.
27. Kamath-Loeb AS, Shen JC, Schmitt MW, Loeb LA (2012). "The Werner syndrome exonuclease facilitates DNA degradation and high fidelity DNA polymerization by human DNA polymerase δ". J. Biol. Chem. 287 (15): 12480–90. doi:10.1074/jbc.M111.332577. PMC 3320997. PMID 22351772.
28. Goto M, Miller RW, Ishikawa Y, Sugano H (1996). "Excess of rare cancers in Werner syndrome (adult progeria)". Cancer Epidemiol. Biomarkers Prev. 5 (4): 239–46. PMID 8722214.
29. Chun SG, Shaeffer DS, Bryant-Greenwood PK (2011). "The Werner's Syndrome RecQ helicase/exonuclease at the nexus of cancer and aging". Hawaii Med J. 70 (3): 52–5. PMC 3071901. PMID 21365542.
30. Agrelo R, Cheng WH, Setien F, Ropero S, Espada J, Fraga MF, Herranz M, Paz MF, Sanchez-Cespedes M, Artiga MJ, Guerrero D, Castells A, von Kobbe C, Bohr VA, Esteller M (2006). "Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer". Proc. Natl. Acad. Sci. U.S.A. 103 (23): 8822–7. doi:10.1073/pnas.0600645103. PMC 1466544. PMID 16723399.
31. von Kobbe C, Karmakar P, Dawut L, Opresko P, Zeng X, Brosh RM, Hickson ID, Bohr VA (June 2002). "Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins". J. Biol. Chem. 277 (24): 22035–44. doi:10.1074/jbc.M200914200. PMID 11919194.
32. Kim ST, Lim DS, Canman CE, Kastan MB (Dec 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". J. Biol. Chem. 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. PMID 10608806.
33. Karmakar P, Piotrowski J, Brosh RM, Sommers JA, Miller SP, Cheng WH, Snowden CM, Ramsden DA, Bohr VA (May 2002). "Werner protein is a target of DNA-dependent protein kinase in vivo and in vitro, and its catalytic activities are regulated by phosphorylation". J. Biol. Chem. 277 (21): 18291–302. doi:10.1074/jbc.M111523200. PMID 11889123.
34. Sharma S, Sommers JA, Wu L, Bohr VA, Hickson ID, Brosh RM (March 2004). "Stimulation of flap endonuclease-1 by the Bloom's syndrome protein". J. Biol. Chem. 279 (11): 9847–56. doi:10.1074/jbc.M309898200. PMID 14688284.
35. Brosh RM, von Kobbe C, Sommers JA, Karmakar P, Opresko PL, Piotrowski J, Dianova I, Dianov GL, Bohr VA (October 2001). "Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity". EMBO J. 20 (20): 5791–801. doi:10.1093/emboj/20.20.5791. PMC 125684. PMID 11598021.
36. Karmakar P, Snowden CM, Ramsden DA, Bohr VA (August 2002). "Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus". Nucleic Acids Res. 30 (16): 3583–91. doi:10.1093/nar/gkf482. PMC 134248. PMID 12177300.
37. Li B, Comai L (September 2000). "Functional interaction between Ku and the werner syndrome protein in DNA end processing". J. Biol. Chem. 275 (37): 28349–52. doi:10.1074/jbc.C000289200. PMID 10880505.
38. Yang Q, Zhang R, Wang XW, Spillare EA, Linke SP, Subramanian D, Griffith JD, Li JL, Hickson ID, Shen JC, Loeb LA, Mazur SJ, Appella E, Brosh RM, Karmakar P, Bohr VA, Harris CC (August 2002). "The processing of Holliday junctions by BLM and WRN helicases is regulated by p53". J. Biol. Chem. 277 (35): 31980–7. doi:10.1074/jbc.M204111200. PMID 12080066.
39. Brosh RM, Karmakar P, Sommers JA, Yang Q, Wang XW, Spillare EA, Harris CC, Bohr VA (September 2001). "p53 Modulates the exonuclease activity of Werner syndrome protein". J. Biol. Chem. 276 (37): 35093–102. doi:10.1074/jbc.M103332200. PMID 11427532.
40. Rodríguez-López AM, Jackson DA, Nehlin JO, Iborra F, Warren AV, Cox LS (February 2003). "Characterisation of the interaction between WRN, the helicase/exonuclease defective in progeroid Werner's syndrome, and an essential replication factor, PCNA". Mech. Ageing Dev. 124 (2): 167–74. doi:10.1016/S0047-6374(02)00131-8. PMID 12633936.
41. Huang S, Beresten S, Li B, Oshima J, Ellis NA, Campisi J (June 2000). "Characterization of the human and mouse WRN 3'-->5' exonuclease". Nucleic Acids Res. 28 (12): 2396–405. doi:10.1093/nar/28.12.2396. PMC 102739. PMID 10871373.
42. Opresko PL, von Kobbe C, Laine JP, Harrigan J, Hickson ID, Bohr VA (October 2002). "Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases". J. Biol. Chem. 277 (43): 41110–9. doi:10.1074/jbc.M205396200. PMID 12181313.
43. Branzei D, Hayashi T, Suzuki H, Masuko T, Onoda F, Heo SJ, Ikeda H, Shimamoto A, Furuichi Y, Seki M, Enomoto T (June 2001). "A novel protein interacts with the Werner's syndrome gene product physically and functionally". J. Biol. Chem. 276 (23): 20364–9. doi:10.1074/jbc.C100035200. PMID 11301316.

Further reading

• Comai L, Li B (2004). "The Werner syndrome protein at the crossroads of DNA repair and apoptosis". Mech Ageing Dev. 125 (8): 521–8. doi:10.1016/j.mad.2004.06.004. PMID 15336909.
• Lee JW, Harrigan J, Opresko PL, Bohr VA (2005). "Pathways and functions of the Werner syndrome protein". Mech Ageing Dev. 126 (1): 79–86. doi:10.1016/j.mad.2004.09.011. PMID 15610765.
• Monnat RJ Jr; Saintigny Y (2004). "Werner syndrome protein--unwinding function to explain disease". Sci Aging Knowledge Environ. 2004 (13): re3. doi:10.1126/sageke.2004.13.re3. PMID 15056797.
• Ozgenc A, Loeb LA (2005). "Current advances in unraveling the function of the Werner syndrome protein". Mutat Res. 577 (1–2): 237–51. doi:10.1016/j.mrfmmm.2005.03.020. PMID 15946710.
• Swanson C, Saintigny Y, Emond MJ, Monnat RJ Jr (2004). "The Werner syndrome protein has separable recombination and survival functions" (PDF). DNA Repair (Amst). 3 (5): 475–82. doi:10.1016/j.dnarep.2004.01.002. PMID 15084309.
• Moser MJ, Oshima J, Monnat RJ (1999). "WRN mutations in Werner syndrome". Hum. Mutat. 13 (4): 271–9. doi:10.1002/(SICI)1098-1004(1999)13:4<271::AID-HUMU2>3.0.CO;2-Q. PMID 10220139.
• Kastan MB, Lim DS (2001). "The many substrates and functions of ATM". Nat. Rev. Mol. Cell Biol. 1 (3): 179–86. doi:10.1038/35043058. PMID 11252893.

External links

• Oshima J, Martin GM, Hisama FM (February 2012). Werner Syndrome. PMID 20301687. NBK1514. In Pagon RA, Bird TD, Dolan CR, et al., eds. (1993). GeneReviews [Internet]. Seattle WA: University of Washington, Seattle.
• GeneCard
• Werner Syndrome Mutational Database