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Crystal structure of the HRDC domain of human Werner syndrome protein, WRN.

Kitano K, Yoshihara N, Hakoshima T
J Biol Chem 282 2717-28 (2007)
Cited: 39 times
EuropePMC logo PMID: 17148451

Abstract

Werner syndrome is a human premature aging disorder characterized by chromosomal instability. The disease is caused by the functional loss of WRN, a member of the RecQ-helicase family that plays an important role in DNA metabolic pathways. WRN contains four structurally folded domains comprising an exonuclease, a helicase, a winged-helix, and a helicase-and-ribonuclease D/C-terminal (HRDC) domain. In contrast to the accumulated knowledge pertaining to the biochemical functions of the three N-terminal domains, the function of C-terminal HRDC remains unknown. In this study, the crystal structure of the human WRN HRDC domain has been determined. The domain forms a bundle of alpha-helices similar to those of Saccharomyces cerevisiae Sgs1 and Escherichia coli RecQ. Surprisingly, the extra ten residues at each of the N and C termini of the domain were found to participate in the domain architecture by forming an extended portion of the first helix alpha1, and a novel looping motif that traverses straight along the domain surface, respectively. The motifs combine to increase the domain surface of WRN HRDC, which is larger than that of Sgs1 and E. coli. In WRN HRDC, neither of the proposed DNA-binding surfaces in Sgs1 or E. coli is conserved, and the domain was shown to lack DNA-binding ability in vitro. Moreover, the domain was shown to be thermostable and resistant to protease digestion, implying independent domain evolution in WRN. Coupled with the unique long linker region in WRN, the WRN HRDC may be adapted to play a distinct function in WRN that involves protein-protein interactions.

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Reviews citing this publication (15)

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  4. The BLM dissolvasome in DNA replication and repair. Manthei KA, Keck JL. Cell Mol Life Sci 70 4067-4084 (2013)
  5. From keys to bulldozers: expanding roles for winged helix domains in nucleic-acid-binding proteins. Harami GM, Gyimesi M, Kovács M. Trends Biochem Sci 38 364-371 (2013)
  6. WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects. Yokote K, Chanprasert S, Lee L, Eirich K, Takemoto M, Watanabe A, Koizumi N, Lessel D, Mori T, Hisama FM, Ladd PD, Angle B, Baris H, Cefle K, Palanduz S, Ozturk S, Chateau A, Deguchi K, Easwar TK, Federico A, Fox A, Grebe TA, Hay B, Nampoothiri S, Seiter K, Streeten E, Piña-Aguilar RE, Poke G, Poot M, Posmyk R, Martin GM, Kubisch C, Schindler D, Oshima J. Hum Mutat 38 7-15 (2017)
  7. Bloom's syndrome: Why not premature aging?: A comparison of the BLM and WRN helicases. de Renty C, Ellis NA. Ageing Res Rev 33 36-51 (2017)
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  9. Human RecQ Helicases in DNA Double-Strand Break Repair. Lu H, Davis AJ. Front Cell Dev Biol 9 640755 (2021)
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  14. Peripheral neuropathies associated with DNA repair disorders. Maguina M, Kang PB, Tsai AC, Pacak CA. Muscle Nerve 67 101-110 (2023)
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Articles citing this publication (22)

  1. Structural basis for DNA strand separation by the unconventional winged-helix domain of RecQ helicase WRN. Kitano K, Kim SY, Hakoshima T. Structure 18 177-187 (2010)
  2. RecQ helicases: multiple structures for multiple functions? Vindigni A, Hickson ID. HFSP J 3 153-164 (2009)
  3. The DNA repair endonuclease XPG interacts directly and functionally with the WRN helicase defective in Werner syndrome. Trego KS, Chernikova SB, Davalos AR, Perry JJ, Finger LD, Ng C, Tsai MS, Yannone SM, Tainer JA, Campisi J, Cooper PK. Cell Cycle 10 1998-2007 (2011)
  4. Domain requirements for DNA unwinding by mycobacterial UvrD2, an essential DNA helicase. Sinha KM, Stephanou NC, Unciuleac MC, Glickman MS, Shuman S. Biochemistry 47 9355-9364 (2008)
  5. Structure and function of the regulatory HRDC domain from human Bloom syndrome protein. Kim YM, Choi BS. Nucleic Acids Res 38 7764-7777 (2010)
  6. Structure and function of the regulatory C-terminal HRDC domain from Deinococcus radiodurans RecQ. Killoran MP, Keck JL. Nucleic Acids Res 36 3139-3149 (2008)
  7. Identification of a coiled coil in werner syndrome protein that facilitates multimerization and promotes exonuclease processivity. Perry JJ, Asaithamby A, Barnebey A, Kiamanesch F, Chen DJ, Han S, Tainer JA, Yannone SM. J Biol Chem 285 25699-25707 (2010)
  8. The HRDC domain of E. coli RecQ helicase controls single-stranded DNA translocation and double-stranded DNA unwinding rates without affecting mechanoenzymatic coupling. Harami GM, Nagy NT, Martina M, Neuman KC, Kovács M. Sci Rep 5 11091 (2015)
  9. Structure of the RecQ C-terminal domain of human Bloom syndrome protein. Kim SY, Hakoshima T, Kitano K. Sci Rep 3 3294 (2013)
  10. Sgs1 truncations induce genome rearrangements but suppress detrimental effects of BLM overexpression in Saccharomyces cerevisiae. Mirzaei H, Syed S, Kennedy J, Schmidt KH. J Mol Biol 405 877-891 (2011)
  11. Mycobacterium smegmatis RqlH defines a novel clade of bacterial RecQ-like DNA helicases with ATP-dependent 3'-5' translocase and duplex unwinding activities. Ordonez H, Unciuleac M, Shuman S. Nucleic Acids Res 40 4604-4614 (2012)
  12. Catalytic activities of Werner protein are affected by adduction with 4-hydroxy-2-nonenal. Czerwińska J, Poznański J, Dębski J, Dębski J, Bukowy Z, Bohr VA, Tudek B, Speina E. Nucleic Acids Res 42 11119-11135 (2014)
  13. On BLM helicase in recombination-mediated telomere maintenance. Rezazadeh S. Mol Biol Rep 40 3049-3064 (2013)
  14. The HRDC domain oppositely modulates the unwinding activity of E. coli RecQ helicase on duplex DNA and G-quadruplex. Teng FY, Wang TT, Guo HL, Xin BG, Sun B, Dou SX, Xi XG, Hou XM. J Biol Chem 295 17646-17658 (2020)
  15. Recruitment of HRDC domain of WRN and BLM to the sites of DNA damage induced by mitomycin C and methyl methanesulfonate. Samanta S, Karmakar P. Cell Biol Int 36 873-881 (2012)
  16. NMR structure of the N-terminal-most HRDC1 domain of RecQ helicase from Deinococcus radiodurans. Liu S, Zhang W, Gao Z, Ming Q, Hou H, Lan W, Wu H, Cao C, Dong Y. FEBS Lett 587 2635-2642 (2013)
  17. Comment Werner helicase wings DNA binding. Hoadley KA, Keck JL. Structure 18 149-151 (2010)
  18. Genetic variation in WRN and ischemic stroke: General population studies and meta-analyses. Christoffersen M, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Exp Gerontol 89 69-77 (2017)
  19. Solution structure of the RecQ C-terminal domain of human Bloom syndrome protein. Park CJ, Ko J, Ryu KS, Choi BS. J Biomol NMR 58 141-147 (2014)
  20. Structure of the helicase core of Werner helicase, a key target in microsatellite instability cancers. Newman JA, Gavard AE, Lieb S, Ravichandran MC, Hauer K, Werni P, Geist L, Böttcher J, Engen JR, Rumpel K, Samwer M, Petronczki M, Gileadi O. Life Sci Alliance 4 e202000795 (2021)
  21. A Toolbox for Site-Specific Labeling of RecQ Helicase With a Single Fluorophore Used in the Single-Molecule Assay. Teng FY, Jiang ZZ, Huang LY, Guo M, Chen F, Hou XM, Xi XG, Xu Y. Front Mol Biosci 7 586450 (2020)
  22. Case Reports A Case Report of Werner's Syndrome With a Novel Mutation From India. Singh A, Ganguly S, Chhabra N, Yadav H, Oshima J. Cureus 12 e8025 (2020)


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