Werner syndrome ATP-dependent helicase
WRN (Werner syndrome) is a human gene that provides instructions for producing Werner protein, which is a type of enzyme called a helicase. 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.
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.
Related conditions
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.
Interactions
Werner syndrome ATP-dependent helicase has been shown to interact with Ku70,[1][2] PCNA,[3][4] DNA-PKcs,[5][6] P53,[7][8] Ku80,[1][2] Flap structure-specific endonuclease 1,[9][10] WRNIP1,[11] Bloom syndrome protein[12] and TERF2.[13]
References
- ^ a b Karmakar, Parimal; Snowden Carey M, Ramsden Dale A, Bohr Vilhelm A (Aug. 2002). "Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus". Nucleic Acids Res. (England) 30 (16): 3583–91. doi:10.1093/nar/gkf482. PMC 134248. PMID 12177300. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=134248.
- ^ a b Li, B; Comai L (Sep. 2000). "Functional interaction between Ku and the werner syndrome protein in DNA end processing". J. Biol. Chem. (UNITED STATES) 275 (37): 28349–52. doi:10.1074/jbc.C000289200. ISSN 0021-9258. PMID 10880505.
- ^ Rodríguez-López, Ana M; Jackson Dean A, Nehlin Jan O, Iborra Francisco, Warren Anna V, Cox Lynne S (Feb. 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. (Ireland) 124 (2): 167–74. doi:10.1016/S0047-6374(02)00131-8. ISSN 0047-6374. PMID 12633936.
- ^ Huang, S; Beresten S, Li B, Oshima J, Ellis N A, Campisi J (Jun. 2000). "Characterization of the human and mouse WRN 3'-->5' exonuclease". Nucleic Acids Res. (ENGLAND) 28 (12): 2396–405. doi:10.1093/nar/28.12.2396. PMC 102739. PMID 10871373. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=102739.
- ^ Kim, S T; Lim D S, Canman C E, Kastan M B (Dec. 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". J. Biol. Chem. (UNITED STATES) 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. ISSN 0021-9258. PMID 10608806.
- ^ Karmakar, Parimal; Piotrowski Jason, Brosh Robert M, Sommers Joshua A, Miller Susan P Lees, Cheng Wen-Hsing, Snowden Carey M, Ramsden Dale A, Bohr Vilhelm A (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. (United States) 277 (21): 18291–302. doi:10.1074/jbc.M111523200. ISSN 0021-9258. PMID 11889123.
- ^ Yang, Qin; Zhang Ran, Wang Xin Wei, Spillare Elisa A, Linke Steven P, Subramanian Deepa, Griffith Jack D, Li Ji Liang, Hickson Ian D, Shen Jiang Cheng, Loeb Lawrence A, Mazur Sharlyn J, Appella Ettore, Brosh Robert M, Karmakar Parimal, Bohr Vilhelm A, Harris Curtis C (Aug. 2002). "The processing of Holliday junctions by BLM and WRN helicases is regulated by p53". J. Biol. Chem. (United States) 277 (35): 31980–7. doi:10.1074/jbc.M204111200. ISSN 0021-9258. PMID 12080066.
- ^ Brosh, R M; Karmakar P, Sommers J A, Yang Q, Wang X W, Spillare E A, Harris C C, Bohr V A (Sep. 2001). "p53 Modulates the exonuclease activity of Werner syndrome protein". J. Biol. Chem. (United States) 276 (37): 35093–102. doi:10.1074/jbc.M103332200. ISSN 0021-9258. PMID 11427532.
- ^ Sharma, Sudha; Sommers Joshua A, Wu Leonard, Bohr Vilhelm A, Hickson Ian D, Brosh Robert M (Mar. 2004). "Stimulation of flap endonuclease-1 by the Bloom's syndrome protein". J. Biol. Chem. (United States) 279 (11): 9847–56. doi:10.1074/jbc.M309898200. ISSN 0021-9258. PMID 14688284.
- ^ Brosh, R M; von Kobbe C, Sommers J A, Karmakar P, Opresko P L, Piotrowski J, Dianova I, Dianov G L, Bohr V A (Oct. 2001). "Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity". EMBO J. (England) 20 (20): 5791–801. doi:10.1093/emboj/20.20.5791. ISSN 0261-4189. PMC 125684. PMID 11598021. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=125684.
- ^ Kawabe Yi, Yi; Branzei D, Hayashi T, Suzuki H, Masuko T, Onoda F, Heo S J, Ikeda H, Shimamoto A, Furuichi Y, Seki M, Enomoto T (Jun. 2001). "A novel protein interacts with the Werner's syndrome gene product physically and functionally". J. Biol. Chem. (United States) 276 (23): 20364–9. doi:10.1074/jbc.C100035200. ISSN 0021-9258. PMID 11301316.
- ^ von Kobbe, Cayetano; Karmakar Parimal, Dawut Lale, Opresko Patricia, Zeng Xianmin, Brosh Robert M, Hickson Ian D, Bohr Vilhelm A (Jun. 2002). "Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins". J. Biol. Chem. (United States) 277 (24): 22035–44. doi:10.1074/jbc.M200914200. ISSN 0021-9258. PMID 11919194.
- ^ Opresko, Patricia L; von Kobbe Cayetano, Laine Jean-Philippe, Harrigan Jeanine, Hickson Ian D, Bohr Vilhelm A (Oct. 2002). "Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases". J. Biol. Chem. (United States) 277 (43): 41110–9. doi:10.1074/jbc.M205396200. ISSN 0021-9258. PMID 12181313.
- 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". 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.
|
PDB gallery
|
|
|
|
2axl: Solution structure of a multifunctional DNA- and protein-binding domain of human Werner syndrome protein
|
|
|
2dgz: Solution structure of the Helicase and RNase D C-terminal domain in Werner syndrome ATP-dependent helicase
|
|
|
2e1e: Crystal structure of the HRDC Domain of Human Werner Syndrome Protein, WRN
|
|
|
2e1f: Crystal structure of the HRDC Domain of Human Werner Syndrome Protein, WRN
|
|
|
2fbv: WRN exonuclease, Mn complex
|
|
|
2fbx: WRN exonuclease, Mg complex
|
|
|
2fby: WRN exonuclease, Eu complex
|
|
|
2fc0: WRN exonuclease, Mn dGMP complex
|
|
|
|
External links
|
|
|
| Excision repair |
Base excision repair/ AP site ( DNA glycosylase, Uracil-DNA glycosylase, Poly ADP ribose polymerase) • Nucleotide excision repair/ ERCC ( XPA, XPB, XPC, XPD/ERCC2, XPE/DDB1, XPF/DDB1, XPG/ERCC5, ERCC1, RPA, RAD23A, RAD23B, Excinuclease)
|
|
| Other forms of repair |
|
|
| Other/ungrouped proteins |
|
|
| Regulation |
|
|
| Other/ungrouped |
8-Oxoguanine • Adaptive response • Meiotic recombination checkpoint • RecF pathway
DNA helicase: BLM · WRN
FANC proteins: core protein complex ( FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM), FANCD1, FANCD2, FANCI, FANCJ, FANCN
|
|
|
see also DNA repair-deficiency disorder
B bsyn: dna (repl, cycl, reco, repr) · tscr (fact, tcrg, nucl, rnat, rept, ptts) · tltn (risu, pttl, nexn) · dnab, rnab/runp · stru (domn, 1°, 2°, 3°, 4°)
|
|