Werner syndrome ATP-dependent helicase
|, RECQ3, RECQL2, RECQL3, Werner syndrome RecQ like helicase|
|RNA expression pattern|
|View/Edit Human||View/Edit Mouse|
"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. 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.
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 reparation of double stranded breaks, nonhomologous end joining, and base excision repair. WRN may also be important in telomere maintenance and replication, especially the replication of the G-rich sequences.
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 in nucleoplasm and 0.12 at nucleoli. 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.
The amino terminus of WRN is involved in both helicase and nuclease activities, while the carboxyl-terminus interacts with p53, an important tumor suppressor. 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. mRNA that codes for WRN has been identified in most human tissues.
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.
Methylation of WRN causes the gene to turn off. This suppresses the production of the WRN protein and its functions in DNA repair.
Werner syndrome is caused by mutations in the WRN gene. 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. 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. Researchers are still determining how these mutations cause the appearance of premature aging seen in Werner syndrome.
WRN deficiencies in cancer
Cells expressing limiting amounts of WRN have elevated mutation frequencies compared with wildtype cells. 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.
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.
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. This hypermethylation caused reduced protein expression of WRN, a common event in tumorigenesis.
|Cancer||Frequency of reduction in cancer|
|Non-small cell lung cancer||37.5%|
|Acute myeloblastic leukemia||4.8%|
Werner syndrome ATP-dependent helicase has been shown to interact with:
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- Carol Bernstein and Harris Bernstein (2015). Epigenetic Reduction of DNA Repair in Progression to Cancer, Advances in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-2209-8, InTech, Available from: http://www.intechopen.com/books/advances-in-dna-repair/epigenetic-reduction-of-dna-repair-in-progression-to-cancer
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- 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.
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- 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.
- 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.
- 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.
- 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.
- 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.
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- 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.
- 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.
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- 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.
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- 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.
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- Swanson C, Saintigny Y, Emond MJ, Monnat RJ Jr (2004). "The Werner syndrome protein has separable recombination and survival functions". 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.