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Studying Werner syndrome to elucidate mechanisms and therapeutics of human aging and age-related diseases

  • Sofie Lautrup
  • Domenica Caponio
  • Hoi-Hung Cheung
  • Claudia Piccoli
  • Tinna Stevnsner
  • Wai-Yee Chan
  • Evandro F. FangEmail author
Review Article

Abstract

Aging is a natural and unavoidable part of life. However, aging is also the primary driver of the dominant human diseases, such as cardiovascular disease, cancer, and neurodegenerative diseases, including Alzheimer’s disease. Unraveling the sophisticated molecular mechanisms of the human aging process may provide novel strategies to extend ‘healthy aging’ and the cure of human aging-related diseases. Werner syndrome (WS), is a heritable human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. As a classical premature aging disease, etiological exploration of WS can shed light on the mechanisms of normal human aging and facilitate the development of interventional strategies to improve healthspan. Here, we summarize the latest progress of the molecular understandings of WRN protein, highlight the advantages of using different WS model systems, including Caenorhabditis elegans, Drosophila melanogaster and induced pluripotent stem cell (iPSC) systems. Further studies on WS will propel drug development for WS patients, and possibly also for normal age-related diseases.

Keywords

Aging Premature aging Werner syndrome NAD+ Mitophagy Hallmarkers of aging DNA repair 

Notes

Acknowledgements

We acknowledge the work of the many researchers whose published papers we were unable to cite due to space limitations. We thank Prof. Vilhelm Bohr at the National Institute on Aging for critical reading of the manuscript. This research was supported by the HELSE SøR-ØST, Norway (E.F.F., #2017056), The Research Council of Norway (E.F.F., #262175 and #277813), and The Hong Kong General Research Fund (H.H.C. and W.Y.C., #Project Number 14121618) of the Research Grants Council. The E.F.F. Laboratory has CRADA arrangements with ChromaDex.

References

  1. Ahn B, Harrigan JA, Indig FE, Wilson DM III, Bohr VA (2004) Regulation of WRN helicase activity in human base excision repair. J Biol Chem 279:53465–53474CrossRefPubMedGoogle Scholar
  2. Aumailley L, Garand C, Dubois MJ, Johnson FB, Marette A, Lebel M (2015) Metabolic and phenotypic differences between mice producing a Werner syndrome helicase mutant protein and Wrn null mice. PLoS ONE 10:e0140292CrossRefPubMedPubMedCentralGoogle Scholar
  3. Berube J, Garand C, Lettre G, Lebel M (2013) The non-synonymous polymorphism at position 114 of the WRN protein affects cholesterol efflux in vitro and correlates with cholesterol levels in vivo. Exp Gerontol 48:533–538CrossRefPubMedGoogle Scholar
  4. Bohr VA (2005) Deficient DNA repair in the human progeroid disorder, Werner syndrome. Mutat Res 577:252–259CrossRefPubMedGoogle Scholar
  5. Bohr VA, Brosh RM Jr, von Kobbe C, Opresko P, Karmakar P (2002) Pathways defective in the human premature aging disease Werner syndrome. Biogerontology 3:89–94CrossRefPubMedGoogle Scholar
  6. Bolterstein E, Rivero R, Marquez M, McVey M (2014) The Drosophila Werner exonuclease participates in an exonuclease-independent response to replication stress. Genetics 197:643–652CrossRefPubMedPubMedCentralGoogle Scholar
  7. Boubriak I, Mason PA, Clancy DJ, Dockray J, Saunders RD, Cox LS (2009) DmWRNexo is a 3′–5′ exonuclease: phenotypic and biochemical characterization of mutants of the Drosophila orthologue of human WRN exonuclease. Biogerontology 10:267–277CrossRefPubMedGoogle Scholar
  8. Brosh RM Jr, Bohr VA (2002) Roles of the Werner syndrome protein in pathways required for maintenance of genome stability. Exp Gerontol 37:491–506CrossRefPubMedGoogle Scholar
  9. Castro E, Edland SD, Lee L, Ogburn CE, Deeb SS, Brown G, Panduro A, Riestra R, Tilvis R, Louhija J et al (2000) Polymorphisms at the Werner locus: II. 1074Leu/Phe, 1367Cys/Arg, longevity, and atherosclerosis. Am J Med Genet 95:374–380CrossRefPubMedGoogle Scholar
  10. Chandel NS, Jasper H, Ho TT, Passegue E (2016) Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. Nat Cell Biol 18:823–832CrossRefPubMedGoogle Scholar
  11. Chang S (2005) A mouse model of Werner syndrome: what can it tell us about aging and cancer? Int J Biochem Cell Biol 37:991–999CrossRefPubMedGoogle Scholar
  12. Chang S, Multani AS, Cabrera NG, Naylor ML, Laud P, Lombard D, Pathak S, Guarente L, DePinho RA (2004) Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nat Genet 36:877–882CrossRefPubMedGoogle Scholar
  13. Chen L, Oshima J (2002) Werner syndrome. J Biomed Biotechnol 2:46–54CrossRefPubMedPubMedCentralGoogle Scholar
  14. Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvold O, Shafeghati Y, Botha EG, Garg A, Hanson NB, Martin GM et al (2003) LMNA mutations in atypical Werner’s syndrome. Lancet (London, England) 362:440–445CrossRefGoogle Scholar
  15. Chen DT, Jiang X, Akula N, Shugart YY, Wendland JR, Steele CJ, Kassem L, Park JH, Chatterjee N, Jamain S et al (2013) Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder. Mol Psychiatry 18:195–205CrossRefPubMedGoogle Scholar
  16. Cheng WH, Kusumoto R, Opresko PL, Sui X, Huang S, Nicolette ML, Paull TT, Campisi J, Seidman M, Bohr VA (2006) Collaboration of Werner syndrome protein and BRCA1 in cellular responses to DNA interstrand cross-links. Nucleic Acids Res 34:2751–2760CrossRefPubMedPubMedCentralGoogle Scholar
  17. Cheung HH, Liu X, Canterel-Thouennon L, Li L, Edmonson C, Rennert OM (2014) Telomerase protects Werner syndrome lineage-specific stem cells from premature aging. Stem Cell Rep 2:534–546CrossRefGoogle Scholar
  18. Cheung HH, Pei D, Chan WY (2015) Stem cell aging in adult progeria. Cell Regen (London, England) 4:6Google Scholar
  19. Cogger VC, Svistounov D, Warren A, Zykova S, Melvin RG, Solon-Biet SM, O’Reilly JN, McMahon AC, Ballard JW, De Cabo R et al (2014) Liver aging and pseudocapillarization in a Werner syndrome mouse model. J Gerontol Ser A Biol Sci Med Sci 69:1076–1086CrossRefGoogle Scholar
  20. Cox LS, Clancy DJ, Boubriak I, Saunders RD (2007) Modeling Werner syndrome in Drosophila melanogaster: hyper-recombination in flies lacking WRN-like exonuclease. Ann N Y Acad Sci 1119:274–288CrossRefPubMedGoogle Scholar
  21. Crabbe L, Verdun RE, Haggblom CI, Karlseder J (2004) Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science 306:1951–1953CrossRefPubMedGoogle Scholar
  22. Crabbe L, Jauch A, Naeger CM, Holtgreve-Grez H, Karlseder J (2007) Telomere dysfunction as a cause of genomic instability in Werner syndrome. Proc Natl Acad Sci USA 104:2205–2210CrossRefPubMedGoogle Scholar
  23. Croteau DL, Popuri V, Opresko PL, Bohr VA (2014) Human RecQ helicases in DNA repair, recombination, and replication. Annu Rev Biochem 83:519–552CrossRefPubMedPubMedCentralGoogle Scholar
  24. Dallaire A, Garand C, Paquel ER, Mitchell SJ, de Cabo R, Simard MJ, Lebel M (2012) Down regulation of miR-124 in both Werner syndrome DNA helicase mutant mice and mutant Caenorhabditis elegans wrn-1 reveals the importance of this microRNA in accelerated aging. Aging 4:636–647CrossRefPubMedPubMedCentralGoogle Scholar
  25. Dallaire A, Proulx S, Simard MJ, Lebel M (2014) Expression profile of Caenorhabditis elegans mutant for the Werner syndrome gene ortholog reveals the impact of vitamin C on development to increase life span. BMC Genomics 15:940CrossRefPubMedPubMedCentralGoogle Scholar
  26. Das A, Boldogh I, Lee JW, Harrigan JA, Hegde ML, Piotrowski J, de Souza Pinto N, Ramos W, Greenberg MM, Hazra TK et al (2007) The human Werner syndrome protein stimulates repair of oxidative DNA base damage by the DNA glycosylase NEIL1. J Biol Chem 282:26591–26602CrossRefPubMedGoogle Scholar
  27. Fang EF, Scheibye-Knudsen M, Brace LE, Kassahun H, SenGupta T, Nilsen H, Mitchell JR, Croteau DL, Bohr VA (2014) Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 157:882–896CrossRefPubMedPubMedCentralGoogle Scholar
  28. Fang EF, Kassahun H, Croteau DL, Scheibye-Knudsen M, Marosi K, Lu H, Shamanna RA, Kalyanasundaram S, Bollineni RC, Wilson MA et al (2016a) NAD(+) replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab 24:566–581CrossRefPubMedPubMedCentralGoogle Scholar
  29. Fang EF, Scheibye-Knudsen M, Chua KF, Mattson MP, Croteau DL, Bohr VA (2016b) Nuclear DNA damage signalling to mitochondria in ageing. Nat Rev Mol Cell Biol 17:308–321CrossRefPubMedPubMedCentralGoogle Scholar
  30. Fang EF, Lautrup S, Hou Y, Demarest TG, Croteau DL, Mattson MP, Bohr VA (2017) NAD(+) in aging: molecular mechanisms and translational implications. Trends Mol Med 23:899–916CrossRefPubMedGoogle Scholar
  31. Faragher RG, Kill IR, Hunter JA, Pope FM, Tannock C, Shall S (1993) The gene responsible for Werner syndrome may be a cell division “counting” gene. Proc Natl Acad Sci USA 90:12030–12034CrossRefPubMedGoogle Scholar
  32. Friedrich K, Lee L, Leistritz DF, Nurnberg G, Saha B, Hisama FM, Eyman DK, Lessel D, Nurnberg P, Li C et al (2010) WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations. Hum Genet 128:103–111CrossRefPubMedPubMedCentralGoogle Scholar
  33. Gagne JP, Lachapelle S, Garand C, Tsofack SP, Coulombe Y, Caron MC, Poirier GG, Masson JY, Lebel M (2016) Different non-synonymous polymorphisms modulate the interaction of the WRN protein to its protein partners and its enzymatic activities. Oncotarget 7:85680–85696CrossRefPubMedPubMedCentralGoogle Scholar
  34. Goto M, Ishikawa Y, Sugimoto M, Furuichi Y (2013) Werner syndrome: a changing pattern of clinical manifestations in Japan (1917–2008). Biosci Trends 7:13–22PubMedGoogle Scholar
  35. Goto M, Hayata K, Chiba J, Matsuura M, Iwaki-Egawa S, Watanabe Y (2015) Multiplex cytokine analysis of Werner syndrome. Intractable Rare Dis Res 4:190–197CrossRefPubMedPubMedCentralGoogle Scholar
  36. Grandori C, Wu KJ, Fernandez P, Ngouenet C, Grim J, Clurman BE, Moser MJ, Oshima J, Russell DW, Swisshelm K et al (2003) Werner syndrome protein limits MYC-induced cellular senescence. Genes Dev 17:1569–1574CrossRefPubMedPubMedCentralGoogle Scholar
  37. Gray MD, Shen JC, Kamath-Loeb AS, Blank A, Sopher BL, Martin GM, Oshima J, Loeb LA (1997) The Werner syndrome protein is a DNA helicase. Nat Genet 17:100–103CrossRefPubMedGoogle Scholar
  38. Gray MD, Wang L, Youssoufian H, Martin GM, Oshima J (1998) Werner helicase is localized to transcriptionally active nucleoli of cycling cells. Exp Cell Res 242:487–494CrossRefPubMedGoogle Scholar
  39. Harrigan JA, Piotrowski J, Di Noto L, Levine RL, Bohr VA (2007) Metal-catalyzed oxidation of the Werner syndrome protein causes loss of catalytic activities and impaired protein-protein interactions. J Biol Chem 282:36403–36411CrossRefPubMedGoogle Scholar
  40. Hayflick L (1965) The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 37:614–636CrossRefPubMedGoogle Scholar
  41. Hirai M, Suzuki S, Hinokio Y, Yamada T, Yoshizumi S, Suzuki C, Satoh J, Oka Y (2005) WRN gene 1367 Arg allele protects against development of type 2 diabetes mellitus. Diabetes Res Clin Pract 69:287–292CrossRefPubMedGoogle Scholar
  42. Huang S, Li B, Gray MD, Oshima J, Mian IS, Campisi J (1998) The premature ageing syndrome protein, WRN, is a 3′ → 5′ exonuclease. Nat Genet 20:114–116CrossRefPubMedPubMedCentralGoogle Scholar
  43. Huang S, Beresten S, Li B, Oshima J, Ellis NA, Campisi J (2000) Characterization of the human and mouse WRN 3′ → 5′ exonuclease. Nucleic Acids Res 28:2396–2405CrossRefPubMedPubMedCentralGoogle Scholar
  44. Huang S, Lee L, Hanson NB, Lenaerts C, Hoehn H, Poot M, Rubin CD, Chen DF, Yang CC, Juch H et al (2006) The spectrum of WRN mutations in Werner syndrome patients. Hum Mutat 27:558–567CrossRefPubMedPubMedCentralGoogle Scholar
  45. Hyun M, Bohr VA, Ahn B (2008) Biochemical characterization of the WRN-1 RecQ helicase of Caenorhabditis elegans. Biochemistry 47:7583–7593CrossRefPubMedPubMedCentralGoogle Scholar
  46. Ibrahim B, Sheerin AN, Jennert-Burston K, Bird JL, Massala MV, Illsley M, James SE, Faragher RG (2016) Absence of premature senescence in Werner’s syndrome keratinocytes. Exp Gerontol 83:139–147CrossRefPubMedGoogle Scholar
  47. Ishikawa N, Nakamura K, Izumiyama-Shimomura N, Aida J, Ishii A, Goto M, Ishikawa Y, Asaka R, Matsuura M, Hatamochi A et al (2011) Accelerated in vivo epidermal telomere loss in Werner syndrome. Aging (Albany NY) 3:417–429CrossRefGoogle Scholar
  48. Kamath-Loeb A, Loeb LA, Fry M (2012) The Werner syndrome protein is distinguished from the Bloom syndrome protein by its capacity to tightly bind diverse DNA structures. PLoS ONE 7:e30189CrossRefPubMedPubMedCentralGoogle Scholar
  49. Ketting RF, Haverkamp TH, van Luenen HG, Plasterk RH (1999) Mut-7 of C. elegans, required for transposon silencing and RNA interference, is a homolog of Werner syndrome helicase and RNaseD. Cell 99:133–141CrossRefPubMedGoogle Scholar
  50. Kong Y, Cui H, Ramkumar C, Zhang H (2011) Regulation of senescence in cancer and aging. J Aging Res 2011:963172CrossRefPubMedPubMedCentralGoogle Scholar
  51. Kulminski AM, Culminskaya I (2013) Genomics of human health and aging. Age (Dordrecht, Netherlands) 35:455–469CrossRefGoogle Scholar
  52. Kusano K, Berres ME, Engels WR (1999) Evolution of the RECQ family of helicases: a Drosophila homolog, Dmblm, is similar to the human bloom syndrome gene. Genetics 151:1027–1039PubMedPubMedCentralGoogle Scholar
  53. Kusumoto R, Muftuoglu M, Bohr VA (2007) The role of WRN in DNA repair is affected by post-translational modifications. Mech Ageing Dev 128:50–57CrossRefPubMedGoogle Scholar
  54. Lebel M, Leder P (1998) A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity. Proc Natl Acad Sci USA 95:13097–13102CrossRefPubMedGoogle Scholar
  55. Lebel M, Monnat RJ Jr (2018) Werner syndrome (WRN) gene variants and their association with altered function and age-associated diseases. Ageing Res Rev 41:82–97CrossRefPubMedGoogle Scholar
  56. Lebel M, Spillare EA, Harris CC, Leder P (1999) The Werner syndrome gene product co-purifies with the DNA replication complex and interacts with PCNA and topoisomerase I. J Biol Chem 274:37795–37799CrossRefPubMedGoogle Scholar
  57. Lebel M, Cardiff RD, Leder P (2001) Tumorigenic effect of nonfunctional p53 or p21 in mice mutant in the Werner syndrome helicase. Can Res 61:1816–1819Google Scholar
  58. Lebel M, Lavoie J, Gaudreault I, Bronsard M, Drouin R (2003) Genetic cooperation between the Werner syndrome protein and poly(ADP-ribose) polymerase-1 in preventing chromatid breaks, complex chromosomal rearrangements, and cancer in mice. Am J Pathol 162:1559–1569CrossRefPubMedPubMedCentralGoogle Scholar
  59. Lee SJ, Yook JS, Han SM, Koo HS (2004) A Werner syndrome protein homolog affects C. elegans development, growth rate, life span and sensitivity to DNA damage by acting at a DNA damage checkpoint. Development (Cambridge, England) 131:2565–2575CrossRefGoogle Scholar
  60. Lee SJ, Gartner A, Hyun M, Ahn B, Koo HS (2010) The Caenorhabditis elegans Werner syndrome protein functions upstream of ATR and ATM in response to DNA replication inhibition and double-strand DNA breaks. PLoS Genet 6:e1000801CrossRefPubMedPubMedCentralGoogle Scholar
  61. Li B, Iglesias-Pedraz JM, Chen LY, Yin F, Cadenas E, Reddy S, Comai L (2014) Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells. Aging Cell 13:367–378CrossRefPubMedGoogle Scholar
  62. Li Y, Zhang W, Chang L, Han Y, Sun L, Gong X, Tang H, Liu Z, Deng H, Ye Y et al (2016) Vitamin C alleviates aging defects in a stem cell model for Werner syndrome. Protein Cell 7:478–488CrossRefPubMedPubMedCentralGoogle Scholar
  63. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217CrossRefPubMedPubMedCentralGoogle Scholar
  64. Lu H, Fang EF, Sykora P, Kulikowicz T, Zhang Y, Becker KG, Croteau DL, Bohr VA (2014) Senescence induced by RECQL4 dysfunction contributes to Rothmund-Thomson syndrome features in mice. Cell Death Dis 5:e1226CrossRefPubMedPubMedCentralGoogle Scholar
  65. Machwe A, Ganunis R, Bohr VA, Orren DK (2000) Selective blockage of the 3′ → 5′ exonuclease activity of WRN protein by certain oxidative modifications and bulky lesions in DNA. Nucleic Acids Res 28:2762–2770CrossRefPubMedPubMedCentralGoogle Scholar
  66. Machwe A, Karale R, Xu X, Liu Y, Orren DK (2011) The Werner and Bloom syndrome proteins help resolve replication blockage by converting (regressed) holliday junctions to functional replication forks. Biochemistry 50:6774–6788CrossRefPubMedPubMedCentralGoogle Scholar
  67. Maierhofer A, Flunkert J, Oshima J, Martin GM, Haaf T, Horvath S (2017) Accelerated epigenetic aging in Werner syndrome. Aging (Albany NY) 9:1143–1152CrossRefGoogle Scholar
  68. Maity J, Bohr VA, Laskar A, Karmakar P (2014) Transient overexpression of Werner protein rescues starvation induced autophagy in Werner syndrome cells. Biochem Biophys Acta 1842:2387–2394PubMedGoogle Scholar
  69. Marciniak RA, Lombard DB, Johnson FB, Guarente L (1998) Nucleolar localization of the Werner syndrome protein in human cells. Proc Natl Acad Sci USA 95:6887–6892CrossRefPubMedGoogle Scholar
  70. Mason PA, Boubriak I, Robbins T, Lasala R, Saunders R, Cox LS (2013) The Drosophila orthologue of progeroid human WRN exonuclease, DmWRNexo, cleaves replication substrates but is inhibited by uracil or abasic sites: analysis of DmWRNexo activity in vitro. Age (Dordrecht, Netherlands) 35:793–806CrossRefGoogle Scholar
  71. Massip L, Garand C, Turaga RV, Deschenes F, Thorin E, Lebel M (2006) Increased insulin, triglycerides, reactive oxygen species, and cardiac fibrosis in mice with a mutation in the helicase domain of the Werner syndrome gene homologue. Exp Gerontol 41:157–168CrossRefPubMedGoogle Scholar
  72. Massip L, Garand C, Paquet ER, Cogger VC, O’Reilly JN, Tworek L, Hatherell A, Taylor CG, Thorin E, Zahradka P et al (2010) Vitamin C restores healthy aging in a mouse model for Werner syndrome. FASEB J 24:158–172CrossRefPubMedGoogle Scholar
  73. Matsumoto T, Shimamoto A, Goto M, Furuichi Y (1997) Impaired nuclear localization of defective DNA helicases in Werner’s syndrome. Nat Genet 16:335–336CrossRefPubMedGoogle Scholar
  74. Mead S, Uphill J, Beck J, Poulter M, Campbell T, Lowe J, Adamson G, Hummerich H, Klopp N, Ruckert IM et al (2012) Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP. Hum Mol Genet 21:1897–1906CrossRefPubMedGoogle Scholar
  75. Nakayama R, Sato Y, Masutani M, Ogino H, Nakatani F, Chuman H, Beppu Y, Morioka H, Yabe H, Hirose H et al (2008) Association of a missense single nucleotide polymorphism, Cys1367Arg of the WRN gene, with the risk of bone and soft tissue sarcomas in Japan. Cancer Sci 99:333–339CrossRefPubMedGoogle Scholar
  76. Opresko PL, Otterlei M, Graakjaer J, Bruheim P, Dawut L, Kolvraa S, May A, Seidman MM, Bohr VA (2004) The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2. Mol Cell 14:763–774CrossRefPubMedGoogle Scholar
  77. Opresko PL, Calvo JP, von Kobbe C (2007) Role for the Werner syndrome protein in the promotion of tumor cell growth. Mech Ageing Dev 128:423–436CrossRefPubMedGoogle Scholar
  78. Oshima J, Hisama FM (2014) Search and insights into novel genetic alterations leading to classical and atypical Werner syndrome. Gerontology 60:239–246CrossRefPubMedPubMedCentralGoogle Scholar
  79. Oshima J, Campisi J, Tannock TC, Martin GM (1995) Regulation of c-fos expression in senescing Werner syndrome fibroblasts differs from that observed in senescing fibroblasts from normal donors. J Cell Physiol 162:277–283CrossRefPubMedGoogle Scholar
  80. Oshima J, Yu CE, Piussan C, Klein G, Jabkowski J, Balci S, Miki T, Nakura J, Ogihara T, Ells J et al (1996) Homozygous and compound heterozygous mutations at the Werner syndrome locus. Hum Mol Genet 5:1909–1913CrossRefPubMedGoogle Scholar
  81. Oshima J, Sidorova JM, Monnat RJ Jr (2017) Werner syndrome: clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev 33:105–114CrossRefPubMedGoogle Scholar
  82. Pichierri P, Franchitto A, Mosesso P, Palitti F (2001) Werner’s syndrome protein is required for correct recovery after replication arrest and DNA damage induced in S-phase of cell cycle. Mol Biol Cell 12:2412–2421CrossRefPubMedPubMedCentralGoogle Scholar
  83. Rodier F, Campisi J (2011) Four faces of cellular senescence. J Cell Biol 192:547–556CrossRefPubMedPubMedCentralGoogle Scholar
  84. Rodier F, Munoz DP, Teachenor R, Chu V, Le O, Bhaumik D, Coppe JP, Campeau E, Beausejour CM, Kim SH et al (2011) DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J Cell Sci 124:68–81CrossRefPubMedGoogle Scholar
  85. Rodriguez-Lopez AM, Jackson DA, Iborra F, Cox LS (2002) Asymmetry of DNA replication fork progression in Werner’s syndrome. Aging Cell 1:30–39CrossRefPubMedGoogle Scholar
  86. Rodriguez-Lopez AM, Jackson DA, Nehlin JO, Iborra F, Warren AV, Cox LS (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 124:167–174CrossRefPubMedGoogle Scholar
  87. Ryu JS, Koo HS (2016) Roles of Caenorhabditis elegans WRN helicase in DNA damage responses, and a comparison with its mammalian homolog: a mini-review. Gerontology 62:296–303CrossRefPubMedGoogle Scholar
  88. Ryu JS, Koo HS (2017) The Caenorhabditis elegans WRN helicase promotes double-strand DNA break repair by mediating end resection and checkpoint activation. FEBS Lett 591:2155–2166CrossRefPubMedGoogle Scholar
  89. Saha B, Cypro A, Martin GM, Oshima J (2014) Rapamycin decreases DNA damage accumulation and enhances cell growth of WRN-deficient human fibroblasts. Aging Cell 13:573–575CrossRefPubMedPubMedCentralGoogle Scholar
  90. Salk D (1985) In vitro studies of Werner syndrome cells: aberrant growth and chromosome behavior. Basic Life Sci 35:419–426PubMedGoogle Scholar
  91. Salk D, Bryant E, Hoehn H, Johnston P, Martin GM (1985) Growth characteristics of Werner syndrome cells in vitro. Adv Exp Med Biol 190:305–311CrossRefPubMedGoogle Scholar
  92. Saunders RD, Boubriak I, Clancy DJ, Cox LS (2008) Identification and characterization of a Drosophila ortholog of WRN exonuclease that is required to maintain genome integrity. Aging Cell 7:418–425CrossRefPubMedPubMedCentralGoogle Scholar
  93. Scheibye-Knudsen M, Mitchell SJ, Fang EF, Iyama T, Ward T, Wang J, Dunn CA, Singh N, Veith S, Hasan-Olive MM et al (2014) A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in Cockayne syndrome. Cell Metab 20:840–855CrossRefPubMedPubMedCentralGoogle Scholar
  94. Sebastiani P, Solovieff N, Dewan AT, Walsh KM, Puca A, Hartley SW, Melista E, Andersen S, Dworkis DA, Wilk JB et al (2012) Genetic signatures of exceptional longevity in humans. PLoS ONE 7:e29848CrossRefPubMedPubMedCentralGoogle Scholar
  95. Sebastiani P, Bae H, Sun FX, Andersen SL, Daw EW, Malovini A, Kojima T, Hirose N, Schupf N, Puca A et al (2013) Meta-analysis of genetic variants associated with human exceptional longevity. Aging (Albany NY) 5:653–661CrossRefGoogle Scholar
  96. Shamanna RA, Lu H, de Freitas JK, Tian J, Croteau DL, Bohr VA (2016) WRN regulates pathway choice between classical and alternative non-homologous end joining. Nat Commun 7:13785CrossRefPubMedPubMedCentralGoogle Scholar
  97. Shamanna RA, Croteau DL, Lee JH, Bohr VA (2017) Recent advances in understanding Werner syndrome. F1000Res 6:1779CrossRefPubMedPubMedCentralGoogle Scholar
  98. Shen JC, Loeb LA (2000) Werner syndrome exonuclease catalyzes structure-dependent degradation of DNA. Nucleic Acids Res 28:3260–3268CrossRefPubMedPubMedCentralGoogle Scholar
  99. Shen M, Zheng T, Lan Q, Zhang Y, Zahm SH, Wang SS, Holford TR, Leaderer B, Yeager M, Welch R et al (2006) Polymorphisms in DNA repair genes and risk of non-Hodgkin lymphoma among women in Connecticut. Hum Genet 119:659–668CrossRefPubMedGoogle Scholar
  100. Shimamoto A, Kagawa H, Zensho K, Sera Y, Kazuki Y, Osaki M, Oshimura M, Ishigaki Y, Hamasaki K, Kodama Y et al (2014) Reprogramming suppresses premature senescence phenotypes of Werner syndrome cells and maintains chromosomal stability over long-term culture. PLoS ONE 9:e112900CrossRefPubMedPubMedCentralGoogle Scholar
  101. Shimamoto A, Yokote K, Tahara H (2015) Werner Syndrome-specific induced pluripotent stem cells: recovery of telomere function by reprogramming. Front Genet 6:10CrossRefPubMedPubMedCentralGoogle Scholar
  102. Sild M, Koca C, Bendixen MH, Frederiksen H, McGue M, Kolvraa S, Christensen K, Nexo B (2006) Possible associations between successful aging and polymorphic markers in the Werner gene region. Ann N Y Acad Sci 1067:309–310CrossRefPubMedGoogle Scholar
  103. Suzuki T, Shiratori M, Furuichi Y, Matsumoto T (2001) Diverged nuclear localization of Werner helicase in human and mouse cells. Oncogene 20:2551–2558CrossRefPubMedGoogle Scholar
  104. Szekely AM, Bleichert F, Numann A, Van Komen S, Manasanch E, Ben Nasr A, Canaan A, Weissman SM (2005) Werner protein protects nonproliferating cells from oxidative DNA damage. Mol Cell Biol 25:10492–10506CrossRefPubMedPubMedCentralGoogle Scholar
  105. Tadokoro T, Rybanska-Spaeder I, Kulikowicz T, Dawut L, Oshima J, Croteau DL, Bohr VA (2013) Functional deficit associated with a missense Werner syndrome mutation. DNA Repair 12:414–421CrossRefPubMedPubMedCentralGoogle Scholar
  106. Talaei F, van Praag VM, Henning RH (2013) Hydrogen sulfide restores a normal morphological phenotype in Werner syndrome fibroblasts, attenuates oxidative damage and modulates mTOR pathway. Pharmacol Res 74:34–44CrossRefPubMedGoogle Scholar
  107. Uhrhammer NA, Lafarge L, Dos Santos L, Domaszewska A, Lange M, Yang Y, Aractingi S, Bessis D, Bignon YJ (2006) Werner syndrome and mutations of the WRN and LMNA genes in France. Hum Mutat 27:718–719CrossRefPubMedGoogle Scholar
  108. Wang L, Ogburn CE, Ware CB, Ladiges WC, Youssoufian H, Martin GM, Oshima J (2000) Cellular Werner phenotypes in mice expressing a putative dominant-negative human WRN gene. Genetics 154:357–362PubMedPubMedCentralGoogle Scholar
  109. Wang S, Liu Z, Ye Y, Li B, Liu T, Zhang W, Liu GH, Zhang YA, Qu J, Xu D et al (2018) Ectopic hTERT expression facilitates reprograming of fibroblasts derived from patients with Werner syndrome as a WS cellular model. Cell Death Dis 9:923CrossRefPubMedPubMedCentralGoogle Scholar
  110. Wrighton KH (2015) Stem cells: SIRT7, the UPR and HSC ageing. Nat Rev Mol Cell Biol 16:266–267CrossRefPubMedGoogle Scholar
  111. Wu Z, Zhang W, Song M, Wang W, Wei G, Li W, Lei J, Huang Y, Sang Y, Chan P et al (2018) Differential stem cell aging kinetics in Hutchinson–Gilford progeria syndrome and Werner syndrome. Protein Cell 9:333–350CrossRefPubMedPubMedCentralGoogle Scholar
  112. Wyllie FS, Jones CJ, Skinner JW, Haughton MF, Wallis C, Wynford-Thomas D, Faragher RG, Kipling D (2000) Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts. Nat Genet 24:16–17CrossRefPubMedGoogle Scholar
  113. Yasuda H, Nagata M, Hara K, Moriyama H, Yokono K (2010) Biguanide, but not thiazolidinedione, improved insulin resistance in Werner syndrome. J Am Geriatr Soc 58:181–182CrossRefPubMedGoogle Scholar
  114. Ye L, Miki T, Nakura J, Oshima J, Kamino K, Rakugi H, Ikegami H, Higaki J, Edland SD, Martin GM et al (1997) Association of a polymorphic variant of the Werner helicase gene with myocardial infarction in a Japanese population. Am J Med Genet 68:494–498CrossRefPubMedGoogle Scholar
  115. Yokote K, Saito Y (2008) Extension of the life span in patients with Werner syndrome. J Am Geriatr Soc 56:1770–1771CrossRefPubMedGoogle Scholar
  116. Yokote K, Hara K, Mori S, Kadowaki T, Saito Y, Goto M (2004) Dysadipocytokinemia in Werner syndrome and its recovery by treatment with pioglitazone. Diabetes Care 27:2562–2563CrossRefPubMedGoogle Scholar
  117. Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S et al (1996) Positional cloning of the Werner’s syndrome gene. Science 272:258–262CrossRefPubMedGoogle Scholar
  118. Zhang W, Li J, Suzuki K, Qu J, Wang P, Zhou J, Liu X, Ren R, Xu X, Ocampo A et al (2015) A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science 348:1160–1163CrossRefPubMedPubMedCentralGoogle Scholar
  119. Zhu X, Zhang G, Kang L, Guan H (2015) Epigenetic regulation of Werner syndrome gene in age-related cataract. J Ophthalmol 2015:579695PubMedPubMedCentralGoogle Scholar

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© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Clinical Molecular Biology, Faculty of MedicineUniversity of OsloOsloNorway
  2. 2.EpiGenAkershus University HospitalLørenskogNorway
  3. 3.Department of Clinical and Experimental MedicineUniversity of Foggia Medical SchoolFoggiaItaly
  4. 4.CUHK-CAS GIBH Joint Research Laboratory on Stem Cell and Regenerative Medicine, School of Biomedical Sciences, Faculty of MedicineThe Chinese University of Hong KongShatinChina
  5. 5.Laboratory of Pre-clinical and Translational Research, IRCCS-CROBReferral Cancer Center of BasilicataRionero in VultureItaly
  6. 6.Department of Molecular Biology and Genetics, Danish Aging Research CenterUniversity of AarhusAarhus CDenmark

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