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PLOS Genetics  2007 

Human Subtelomeric WASH Genes Encode a New Subclass of the WASP Family

DOI: 10.1371/journal.pgen.0030237

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Subtelomeres are duplication-rich, structurally variable regions of the human genome situated just proximal of telomeres. We report here that the most terminally located human subtelomeric genes encode a previously unrecognized third subclass of the Wiskott-Aldrich Syndrome Protein family, whose known members reorganize the actin cytoskeleton in response to extracellular stimuli. This new subclass, which we call WASH, is evolutionarily conserved in species as diverged as Entamoeba. We demonstrate that WASH is essential in Drosophila. WASH is widely expressed in human tissues, and human WASH protein colocalizes with actin in filopodia and lamellipodia. The VCA domain of human WASH promotes actin polymerization by the Arp2/3 complex in vitro. WASH duplicated to multiple chromosomal ends during primate evolution, with highest copy number reached in humans, whose WASH repertoires vary. Thus, human subtelomeres are not genetic junkyards, and WASH's location in these dynamic regions could have advantageous as well as pathologic consequences.


[1]  Cenci G, Ciapponi L, Gatti M (2005) The mechanism of telomere protection: a comparison between Drosophila and humans. Chromosoma 114: 135–145.
[2]  Koering CE, Pollice A, Zibella MP, Bauwens S, Puisieux A, et al. (2002) Human telomeric position effect is determined by chromosomal context and telomeric chromatin integrity. EMBO Rep 3: 1055–1061.
[3]  Pedram M, Sprung CN, Gao Q, Lo AW, Reynolds GE, et al. (2006) Telomere position effect and silencing of transgenes near telomeres in the mouse. Mol Cell Biol 26: 1865–1878.
[4]  Linardopoulou EV, Williams EM, Fan Y, Friedman C, Young JM, et al. (2005) Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication. Nature 437: 94–100.
[5]  Matise TC, Sachidanandam R, Clark AG, Kruglyak L, Wijsman E, et al. (2003) A 3.9-centimorgan-resolution human single-nucleotide polymorphism linkage map and screening set. Am J Hum Genet 73: 271–284.
[6]  d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, et al. (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426: 194–198.
[7]  Rudd MK, Friedman C, Parghi SS, Linardopoulou EV, Hsu L, et al. (2007) Elevated rates of sister chromatid exchange at chromosome ends. PLoS Genet 3: e32. doi:10.1371/journal.pgen.0030032.
[8]  Barry JD, Ginger ML, Burton P, McCulloch R (2003) Why are parasite contingency genes often associated with telomeres? Int J Parasitol 33: 29–45.
[9]  Fabre E, Muller H, Therizols P, Lafontaine I, Dujon B, et al. (2005) Comparative genomics in hemiascomycete yeasts: evolution of sex, silencing, and subtelomeres. Mol Biol Evol 22: 856–873.
[10]  Ravnan JB, Tepperberg JH, Papenhausen P, Lamb AN, Hedrick J, et al. (2006) Subtelomere FISH analysis of 11 688 cases: an evaluation of the frequency and pattern of subtelomere rearrangements in individuals with developmental disabilities. J Med Genet 43: 478–489.
[11]  Ciccodicola A, D'Esposito M, Esposito T, Gianfrancesco F, Migliaccio C, et al. (2000) Differentially regulated and evolved genes in the fully sequenced Xq/Yq pseudoautosomal region. Hum Mol Genet 9: 395–401.
[12]  Gianfrancesco F, Falco G, Esposito T, Rocchi M, D'Urso M (2001) Characterization of the murine orthologue of a novel human subtelomeric multigene family. Cytogenet Cell Genet 94: 98–100.
[13]  Hansen M, Hsu AL, Dillin A, Kenyon C (2005) New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a genomic RNAi screen. PLoS Genet 1: e17. doi:10.1371/journal.pgen.0010017.
[14]  Marchand JB, Kaiser DA, Pollard TD, Higgs HN (2001) Interaction of WASP/Scar proteins with actin and vertebrate Arp2/3 complex. Nat Cell Biol 3: 76–82.
[15]  Bompard G, Caron E (2004) Regulation of WASP/WAVE proteins: making a long story short. J Cell Biol 166: 957–962.
[16]  Millard TH, Sharp SJ, Machesky LM (2004) Signalling to actin assembly via the WASP (Wiskott-Aldrich syndrome protein)-family proteins and the Arp2/3 complex. Biochem J 380: 1–17.
[17]  Yamaguchi H, Condeelis J (2007) Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim Biophys Acta 1773: 642–652..
[18]  Takenawa T, Suetsugu S (2007) The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol 8: 37–48.
[19]  Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, et al. (2004) A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A 101: 6062–6067.
[20]  Paunola E, Mattila PK, Lappalainen P (2002) WH2 domain: a small, versatile adapter for actin monomers. FEBS Lett 513: 92–97.
[21]  Panchal SC, Kaiser DA, Torres E, Pollard TD, Rosen MK (2003) A conserved amphipathic helix in WASP/Scar proteins is essential for activation of Arp2/3 complex. Nat Struct Biol 10: 591–598.
[22]  Caron E (2003) Regulation by phosphorylation. Yet another twist in the WASP story. Dev Cell 4: 772–773.
[23]  Pollard TD, Borisy GG (2003) Cellular motility driven by assembly and disassembly of actin filaments. Cell 112: 453–465.
[24]  Zalevsky J, Lempert L, Kranitz H, Mullins RD (2001) Different WASP family proteins stimulate different Arp2/3 complex-dependent actin-nucleating activities. Curr Biol 11: 1903–1913.
[25]  Ben-Yaacov S, Le Borgne R, Abramson I, Schweisguth F, Schejter ED (2001) Wasp, the Drosophila Wiskott-Aldrich syndrome gene homologue, is required for cell fate decisions mediated by Notch signaling. J Cell Biol 152: 1–13.
[26]  Zallen JA, Cohen Y, Hudson AM, Cooley L, Wieschaus E, et al. (2002) SCAR is a primary regulator of Arp2/3-dependent morphological events in Drosophila. J Cell Biol 156: 689–701.
[27]  Tomancak P, Beaton A, Weiszmann R, Kwan E, Shu S, et al. (2002) Systematic determination of patterns of gene expression during Drosophila embryogenesis. Genome Biol 3: RESEARCH0088.
[28]  Spradling AC, Stern D, Beaton A, Rhem EJ, Laverty T, et al. (1999) The Berkeley Drosophila Genome Project gene disruption project: Single P-element insertions mutating 25% of vital Drosophila genes. Genetics 153: 135–177.
[29]  Vartiainen MK, Machesky LM (2004) The WASP-Arp2/3 pathway: genetic insights. Curr Opin Cell Biol 16: 174–181.
[30]  Li R (1997) Bee1, a yeast protein with homology to Wiscott-Aldrich syndrome protein, is critical for the assembly of cortical actin cytoskeleton. J Cell Biol 136: 649–658.
[31]  Kim S, Shilagardi K, Zhang S, Hong SN, Sens KL, et al. (2007) A critical function for the actin cytoskeleton in targeted exocytosis of prefusion vesicles during myoblast fusion. Dev Cell 12: 571–586.
[32]  Massarwa R, Carmon S, Shilo BZ, Schejter ED (2007) WIP/WASp-based actin-polymerization machinery is essential for myoblast fusion in Drosophila. Dev Cell 12: 557–569.
[33]  Schafer G, Weber S, Holz A, Bogdan S, Schumacher S, et al. (2007) The Wiskott-Aldrich syndrome protein (WASP) is essential for myoblast fusion in Drosophila. Dev Biol 304: 664–674.
[34]  Hochheimer A, Zhou S, Zheng S, Holmes MC, Tjian R (2002) TRF2 associates with DREF and directs promoter-selective gene expression in Drosophila. Nature 420: 439–445.
[35]  Shumaker DK, Kuczmarski ER, Goldman RD (2003) The nucleoskeleton: lamins and actin are major players in essential nuclear functions. Curr Opin Cell Biol 15: 358–366.
[36]  Suetsugu S, Takenawa T (2003) Translocation of N-WASP by nuclear localization and export signals into the nucleus modulates expression of HSP90. J Biol Chem 278: 42515–42523.
[37]  Wu X, Yoo Y, Okuhama NN, Tucker PW, Liu G, et al. (2006) Regulation of RNA-polymerase-II-dependent transcription by N-WASP and its nuclear-binding partners. Nat Cell Biol 8: 756–763.
[38]  Snapper SB, Takeshima F, Anton I, Liu CH, Thomas SM, et al. (2001) N-WASP deficiency reveals distinct pathways for cell surface projections and microbial actin-based motility. Nat Cell Biol 3: 897–904.
[39]  Yan C, Martinez-Quiles N, Eden S, Shibata T, Takeshima F, et al. (2003) WAVE2 deficiency reveals distinct roles in embryogenesis and Rac-mediated actin-based motility. EMBO J 22: 3602–3612.
[40]  Soderling SH, Langeberg LK, Soderling JA, Davee SM, Simerly R, et al. (2003) Loss of WAVE-1 causes sensorimotor retardation and reduced learning and memory in mice. Proc Natl Acad Sci U S A 100: 1723–1728.
[41]  Zhu Q, Watanabe C, Liu T, Hollenbaugh D, Blaese RM, et al. (1997) Wiskott-Aldrich syndrome/X-linked thrombocytopenia: WASP gene mutations, protein expression, and phenotype. Blood 90: 2680–2689.
[42]  Ochs HD, Thrasher AJ (2006) The Wiskott-Aldrich syndrome. J Allergy Clin Immunol 117: 725–738.
[43]  Leirdal M, Shadidy M, Rosok O, Sioud M (2004) Identification of genes differentially expressed in breast cancer cell line SKBR3: potential identification of new prognostic biomarkers. Int J Mol Med 14: 217–222.
[44]  Koszul R, Dujon B, Fischer G (2006) Stability of large segmental duplications in the yeast genome. Genetics 172: 2211–2222.
[45]  Voigt H, Guillen N (1999) New insights into the role of the cytoskeleton in phagocytosis of . Cell Microbiol 1: 195–203.
[46]  Munter S, Way M, Frischknecht F (2006) Signaling during pathogen infection. Sci STKE 2006: re5.
[47]  Franco-Barraza J, Zamudio-Meza H, Franco E, del Carmen Dominguez-Robles M, Villegas-Sepulveda N, et al. (2006) Rho signaling in modulates actomyosin-dependent activities stimulated during invasive behavior. Cell Motil Cytoskeleton 63: 117–131.


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