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Review

Emerging Roles of ATRX in Cancer

, &
Pages 1365-1378 | Received 11 May 2015, Accepted 13 Aug 2015, Published online: 08 Dec 2015

References

  • Stayton CL , DabovicB , GulisanoMet al. Cloning and characterization of a new human Xq13 gene, encoding a putative helicase . Hum. Mol. Genet.3 ( 11 ), 1957 – 1964 ( 1994 ).
  • Picketts DJ , HiggsDR , BachooS , BlakeDJ , QuarrellOW , GibbonsRJ . ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome . Hum. Mol. Genet.5 ( 12 ), 1899 – 1907 ( 1996 ).
  • Villard L , LossiAM , CardosoCet al. Determination of the genomic structure of the XNP/ATRX gene encoding a potential zinc finger helicase . Genomics43 ( 2 ), 149 – 155 ( 1997 ).
  • Lee NG , HongYK , YuSY , HanSY , GeumD , ChoKS . dXNP, a Drosophila homolog of XNP/ATRX, induces apoptosis via Jun-N-terminal kinase activation . FEBS Lett.581 ( 14 ), 2625 – 2632 ( 2007 ).
  • Villard L , FontesM , EwbankJJ . Characterization of xnp-1, a Caenorhabditis elegans gene similar to the human XNP/ATR-X gene . Gene236 ( 1 ), 13 – 19 ( 1999 ).
  • Gecz J , PollardH , ConsalezGet al. Cloning and expression of the murine homologue of a putative human X-linked nuclear protein gene closely linked to PGK1 in Xq13.3 . Hum. Mol. Genet.3 ( 1 ), 39 – 44 ( 1994 ).
  • Eisen JA , SwederKS , HanawaltPC . Evolution of the SNF2 family of proteins: subfamilies with distinct sequences and functions . Nucl. Acids Res.23 ( 14 ), 2715 – 2723 ( 1995 ).
  • Carlson M , LaurentBC . The SNF/SWI family of global transcriptional activators . Curr. Opin. Cell Biol.6 ( 3 ), 396 – 402 ( 1994 ).
  • Argentaro A , YangJC , ChapmanLet al. Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX . Proc. Natl Acad. Sci. USA104 ( 29 ), 11939 – 11944 ( 2007 ).
  • Xie S , WangZ , OkanoMet al. Cloning, expression and chromosome locations of the human DNMT3 gene family . Gene236 ( 1 ), 87 – 95 ( 1999 ).
  • Aapola U , KawasakiK , ScottHSet al. Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, related to the cytosine-5-methyltransferase 3 gene family . Genomics65 ( 3 ), 293 – 298 ( 2000 ).
  • Picketts DJ , TastanAO , HiggsDR , GibbonsRJ . Comparison of the human and murine ATRX gene identifies highly conserved, functionally important domains . Mamm. Genome9 ( 5 ), 400 – 403 ( 1998 ).
  • Gibbons RJ , BachooS , PickettsDJet al. Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain . Nat. Genet.17 ( 2 ), 146 – 148 ( 1997 ).
  • Xue Y , GibbonsR , YanZet al. The ATRX syndrome protein forms a chromatin-remodeling complex with DAXX and localizes in promyelocytic leukemia nuclear bodies . Proc. Natl Acad. Sci. USA100 ( 19 ), 10635 – 10640 ( 2003 ).
  • Tang J , WuS , LiuHet al. A novel transcription regulatory complex containing death domain-associated protein and the ATR-X syndrome protein . J. Biol. Chem.279 ( 19 ), 20369 – 20377 ( 2004 ).
  • Berube NG , SmeenkCA , PickettsDJ . Cell cycle-dependent phosphorylation of the ATRX protein correlates with changes in nuclear matrix and chromatin association . Hum. Mol. Genet.9 ( 4 ), 539 – 547 ( 2000 ).
  • Mcdowell TL , GibbonsRJ , SutherlandHet al. Localization of a putative transcriptional regulator (ATRX) at pericentromeric heterochromatin and the short arms of acrocentric chromosomes . Proc. Natl Acad. Sci. USA96 ( 24 ), 13983 – 13988 ( 1999 ).
  • Nan X , HouJ , MacleanAet al. Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation . Proc. Natl Acad. Sci. USA104 ( 8 ), 2709 – 2714 ( 2007 ).
  • Baumann C , De La FuenteR . ATRX marks the inactive X chromosome (Xi) in somatic cells and during imprinted X chromosome inactivation in trophoblast stem cells . Chromosoma118 ( 2 ), 209 – 222 ( 2009 ).
  • Sarma K , Cifuentes-RojasC , ErgunAet al. ATRX directs binding of PRC2 to Xist RNA and Polycomb targets . Cell159 ( 4 ), 869 – 883 ( 2014 ).
  • Ratnakumar K , DuarteLF , LeroyGet al. ATRX-mediated chromatin association of histone variant macroH2A1 regulates alpha-globin expression . Genes Dev.26 ( 5 ), 433 – 438 ( 2012 ).
  • Lewis J , BirdA . DNA methylation and chromatin structure . FEBS Lett.285 ( 2 ), 155 – 159 ( 1991 ).
  • Kourmouli N , JeppesenP , MahadevhaiahSet al. Heterochromatin and tri-methylated lysine 20 of histone H4 in animals . J. Cell Sci.117 ( Pt 12 ), 2491 – 2501 ( 2004 ).
  • Schotta G , LachnerM , SarmaKet al. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin . Genes Dev.18 ( 11 ), 1251 – 1262 ( 2004 ).
  • Lechner MS , SchultzDC , NegorevD , MaulGG , RauscherFJ3rd . The mammalian heterochromatin protein 1 binds diverse nuclear proteins through a common motif that targets the chromoshadow domain . Biochem. Biophys. Res. Commun.331 ( 4 ), 929 – 937 ( 2005 ).
  • Ritchie K , SeahC , MoulinJ , IsaacC , DickF , BerubeNG . Loss of ATRX leads to chromosome cohesion and congression defects . J. Cell Biol.180 ( 2 ), 315 – 324 ( 2008 ).
  • Wong LH , McghieJD , SimMet al. ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells . Genome Res.20 ( 3 ), 351 – 360 ( 2010 ).
  • Huh MS , Price O’deaT , OuaziaDet al. Compromised genomic integrity impedes muscle growth after Atrx inactivation . J. Clin. Invest.122 ( 12 ), 4412 – 4423 ( 2012 ).
  • Kourmouli N , SunYM , Van Der SarS , SinghPB , BrownJP . Epigenetic regulation of mammalian pericentric heterochromatin in vivo by HP1 . Biochem. Biophys. Res. Commun.337 ( 3 ), 901 – 907 ( 2005 ).
  • Eustermann S , YangJC , LawMJet al. Combinatorial readout of histone H3 modifications specifies localization of ATRX to heterochromatin . Nat. Struct. Mol. Biol.18 ( 7 ), 777 – 782 ( 2011 ).
  • Mitson M , KelleyLA , SternbergMJ , HiggsDR , GibbonsRJ . Functional significance of mutations in the Snf2 domain of ATRX . Hum. Mol. Genet.20 ( 13 ), 2603 – 2610 ( 2011 ).
  • Iwase S , XiangB , GhoshSet al. ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome . Nat. Struct. Mol. Biol.18 ( 7 ), 769 – 776 ( 2011 ).
  • Dhayalan A , TamasR , BockIet al. The ATRX-ADD domain binds to H3 tail peptides and reads the combined methylation state of K4 and K9 . Hum. Mol. Genet.20 ( 11 ), 2195 – 2203 ( 2011 ).
  • Kunowska N , RotivalM , YuL , ChoudharyJ , DillonN . Identification of protein complexes that bind to histone H3 combinatorial modifications using super-SILAC and weighted correlation network analysis . Nucl. Acids Res.43 ( 3 ), 1418 – 1432 ( 2015 ).
  • Noh K , MazeI , ZhaoDet al. ATRX tolerates activity-dependent histone H3 methyl/phos switching to maintain repetitive element silencing in neurons . Proc. Natl Acad. Sci. USA112 ( 22 ), 6820 – 6827 ( 2014 ).
  • Sabbattini P , SjobergM , NikicSet al. An H3K9/S10 methyl-phospho switch modulates Polycomb and Pol II binding at repressed genes during differentiation . Mol. Biol. Cell25 ( 6 ), 904 – 915 ( 2014 ).
  • Crosio C , HeitzE , AllisCD , BorrelliE , Sassone-CorsiP . Chromatin remodeling and neuronal response: multiple signaling pathways induce specific histone H3 modifications and early gene expression in hippocampal neurons . J. Cell Sci.116 ( Pt 24 ), 4905 – 4914 ( 2003 ).
  • Baker SA , ChenL , WilkinsAD , YuP , LichtargeO , ZoghbiHY . An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders . Cell152 ( 5 ), 984 – 996 ( 2013 ).
  • Kernohan KD , JiangY , TremblayDCet al. ATRX partners with cohesin and MeCP2 and contributes to developmental silencing of imprinted genes in the brain . Dev. Cell18 ( 2 ), 191 – 202 ( 2010 ).
  • Law MJ , LowerKM , VoonHPet al. ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner . Cell143 ( 3 ), 367 – 378 ( 2010 ).
  • Zhao J , BacollaA , WangG , VasquezKM . Non-B DNA structure-induced genetic instability and evolution . Cell. Mol. Life Sci.67 ( 1 ), 43 – 62 ( 2010 ).
  • Lipps HJ , RhodesD . G-quadruplex structures: in vivo evidence and function . Trends Cell Biol.19 ( 8 ), 414 – 422 ( 2009 ).
  • Biffi G , TannahillD , MccaffertyJ , BalasubramanianS . Quantitative visualization of DNA G-quadruplex structures in human cells . Nat. Chem.5 ( 3 ), 182 – 186 ( 2013 ).
  • Levy MA , KernohanKD , JiangY , BerubeNG . ATRX promotes gene expression by facilitating transcriptional elongation through guanine-rich coding regions . Hum. Mol. Genet.24 ( 7 ), 1824 – 1835 ( 2014 ).
  • Ray-Gallet D , QuivyJP , ScampsC , MartiniEM , LipinskiM , AlmouzniG . HIRA is critical for a nucleosome assembly pathway independent of DNA synthesis . Mol. Cell9 ( 5 ), 1091 – 1100 ( 2002 ).
  • Lewis PW , ElsaesserSJ , NohKM , StadlerSC , AllisCD . Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres . Proc. Natl Acad. Sci. USA107 ( 32 ), 14075 – 14080 ( 2010 ).
  • Goldberg AD , BanaszynskiLA , NohKMet al. Distinct factors control histone variant H3.3 localization at specific genomic regions . Cell140 ( 5 ), 678 – 691 ( 2010 ).
  • Drane P , OuararhniK , DepauxA , ShuaibM , HamicheA . The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3 . Genes Dev.24 ( 12 ), 1253 – 1265 ( 2010 ).
  • Kraushaar DC , JinW , MaunakeaA , AbrahamB , HaM , ZhaoK . Genome-wide incorporation dynamics reveal distinct categories of turnover for the histone variant H3.3 . Genome Biol.14 ( 10 ), R121 ( 2013 ).
  • Schwartz BE , AhmadK . Transcriptional activation triggers deposition and removal of the histone variant H3.3 . Genes Dev.19 ( 7 ), 804 – 814 ( 2005 ).
  • Wirbelauer C , BellO , SchubelerD . Variant histone H3.3 is deposited at sites of nucleosomal displacement throughout transcribed genes while active histone modifications show a promoter-proximal bias . Genes Dev.19 ( 15 ), 1761 – 1766 ( 2005 ).
  • Jin C , FelsenfeldG . Nucleosome stability mediated by histone variants H3.3 and H2A.Z . Genes Dev.21 ( 12 ), 1519 – 1529 ( 2007 ).
  • Watson LA , SolomonLA , LiJRet al. Atrx deficiency induces telomere dysfunction, endocrine defects, and reduced life span . J. Clin. Invest.123 ( 5 ), 2049 – 2063 ( 2013 ).
  • Buhler M , HaasW , GygiSP , MoazedD . RNAi-dependent and -independent RNA turnover mechanisms contribute to heterochromatic gene silencing . Cell129 ( 4 ), 707 – 721 ( 2007 ).
  • Schoeftner S , BlascoMA . A ‘higher order’ of telomere regulation: telomere heterochromatin and telomeric RNAs . EMBO J.28 ( 16 ), 2323 – 2336 ( 2009 ).
  • Flynn RL , CoxKE , JeitanyMet al. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors . Science347 ( 6219 ), 273 – 277 ( 2015 ).
  • Sadic D , SchmidtK , GrohSet al. Atrx promotes heterochromatin formation at retrotransposons . EMBO Rep.16 ( 7 ), 836 – 850 ( 2015 ).
  • Voon HP , HughesJR , RodeCet al. ATRX plays a key role in maintaining silencing at interstitial heterochromatic loci and imprinted genes . Cell Rep.11 ( 3 ), 405 – 418 ( 2015 ).
  • Elsasser SJ , NohKM , DiazN , AllisCD , BanaszynskiLA . Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells . Nature522 ( 7555 ), 240 – 244 ( 2015 ).
  • Ishov AM , SotnikovAG , NegorevDet al. PML is critical for ND10 formation and recruits the PML-interacting protein daxx to this nuclear structure when modified by SUMO-1 . J. Cell Biol.147 ( 2 ), 221 – 234 ( 1999 ).
  • Ishov AM , VladimirovaOV , MaulGG . Heterochromatin and ND10 are cell-cycle regulated and phosphorylation-dependent alternate nuclear sites of the transcription repressor DAXX and SWI/SNF protein ATRX . J. Cell Sci.117 ( Pt 17 ), 3807 – 3820 ( 2004 ).
  • Bernardi R , PandolfiPP . Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies . Nat. Rev. Mol. Cell Biol.8 ( 12 ), 1006 – 1016 ( 2007 ).
  • Melnick A , LichtJD . Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia . Blood93 ( 10 ), 3167 – 3215 ( 1999 ).
  • Weidtkamp-Peters S , LenserT , NegorevDet al. Dynamics of component exchange at PML nuclear bodies . J. Cell Sci.121 ( Pt 16 ), 2731 – 2743 ( 2008 ).
  • Chang FT , McghieJD , ChanFLet al. PML bodies provide an important platform for the maintenance of telomeric chromatin integrity in embryonic stem cells . Nucl. Acids Res.41 ( 8 ), 4447 – 4458 ( 2013 ).
  • Corpet A , OlbrichT , GwerderM , FinkD , StuckiM . Dynamics of histone H3.3 deposition in proliferating and senescent cells reveals a DAXX-dependent targeting to PML-NBs important for pericentromeric heterochromatin organization . Cell Cycle13 ( 2 ), 249 – 267 ( 2014 ).
  • Quivy JP , GerardA , CookAJ , RocheD , AlmouzniG . The HP1-p150/CAF-1 interaction is required for pericentric heterochromatin replication and S-phase progression in mouse cells . Nat. Struct. Mol. Biol.15 ( 9 ), 972 – 979 ( 2008 ).
  • Clynes D , JelinskaC , XellaBet al. ATRX dysfunction induces replication defects in primary mouse cells . PLoS ONE9 ( 3 ), e92915 ( 2014 ).
  • Gibbons RJ , HiggsDR . ATRX: taming tandem repeats . Cell Cycle9 ( 23 ), 4605 – 4606 ( 2010 ).
  • Clynes D , HiggsDR , GibbonsRJ . The chromatin remodeller ATRX: a repeat offender in human disease . Trends Biochem. Sci.38 ( 9 ), 461 – 466 ( 2013 ).
  • Leung JW , GhosalG , WangWet al. Alpha thalassemia/mental retardation syndrome X-linked gene product ATRX is required for proper replication restart and cellular resistance to replication stress . J. Biol. Chem.288 ( 9 ), 6342 – 6350 ( 2013 ).
  • Verdun RE , KarlsederJ . The DNA damage machinery and homologous recombination pathway act consecutively to protect human telomeres . Cell127 ( 4 ), 709 – 720 ( 2006 ).
  • Verdun RE , CrabbeL , HaggblomC , KarlsederJ . Functional human telomeres are recognized as DNA damage in G2 of the cell cycle . Mol. Cell20 ( 4 ), 551 – 561 ( 2005 ).
  • Wilhelm T , MagdalouI , BarascuA , TecherH , DebatisseM , LopezBS . Spontaneous slow replication fork progression elicits mitosis alterations in homologous recombination-deficient mammalian cells . Proc. Natl Acad. Sci. USA111 ( 2 ), 763 – 768 ( 2014 ).
  • Crasta K , GanemNJ , DagherRet al. DNA breaks and chromosome pulverization from errors in mitosis . Nature482 ( 7383 ), 53 – 58 ( 2012 ).
  • De La Fuente R , ViveirosMM , WigglesworthK , EppigJJ . ATRX, a member of the SNF2 family of helicase/ATPases, is required for chromosome alignment and meiotic spindle organization in metaphase II stage mouse oocytes . Dev. Biol.272 ( 1 ), 1 – 14 ( 2004 ).
  • Baumann C , ViveirosMM , De La FuenteR . Loss of maternal ATRX results in centromere instability and aneuploidy in the mammalian oocyte and pre-implantation embryo . PLoS Genet.6 ( 9 ), e1001137 ( 2010 ).
  • Ritchie K , WatsonLA , DavidsonB , JiangY , BerubeNG . ATRX is required for maintenance of the neuroprogenitor cell pool in the embryonic mouse brain . Biology Open3 ( 12 ), 1158 – 1163 ( 2014 ).
  • Ganem NJ , PellmanD . Linking abnormal mitosis to the acquisition of DNA damage . J. Cell Biol.199 ( 6 ), 871 – 881 ( 2012 ).
  • Berube NG , JaglaM , SmeenkC , De RepentignyY , KotharyR , PickettsDJ . Neurodevelopmental defects resulting from ATRX overexpression in transgenic mice . Hum. Mol. Genet.11 ( 3 ), 253 – 261 ( 2002 ).
  • Berube NG , MangelsdorfM , JaglaMet al. The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis . J. Clin. Invest.115 ( 2 ), 258 – 267 ( 2005 ).
  • Seah C , LevyMA , JiangYet al. Neuronal death resulting from targeted disruption of the Snf2 protein ATRX is mediated by p53 . J. Neurosci.28 ( 47 ), 12570 – 12580 ( 2008 ).
  • Jang CW , ShibataY , StarmerJ , YeeD , MagnusonT . Histone H3.3 maintains genome integrity during mammalian development . Genes Dev.29 ( 13 ), 1377 – 1392 ( 2015 ).
  • Gibbons RJ , PickettsDJ , VillardL , HiggsDR . Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome) . Cell80 ( 6 ), 837 – 845 ( 1995 ).
  • Gibbons RJ , WadaT , FisherCAet al. Mutations in the chromatin-associated protein ATRX . Hum. Mutat.29 ( 6 ), 796 – 802 ( 2008 ).
  • Berube NG , HealyJ , MedinaCFet al. Patient mutations alter ATRX targeting to PML nuclear bodies . Eur. J. Hum. Genet.16 ( 2 ), 192 – 201 ( 2008 ).
  • Gibbons RJ , PellagattiA , GarrickDet al. Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS) . Nat. Genet.34 ( 4 ), 446 – 449 ( 2003 ).
  • Lacayo NJ , MeshinchiS , KinnunenPet al. Gene expression profiles at diagnosis in de novo childhood AML patients identify FLT3 mutations with good clinical outcomes . Blood104 ( 9 ), 2646 – 2654 ( 2004 ).
  • Rosen DB , HarringtonKH , CordeiroJAet al. AKT signaling as a novel factor associated with in vitro resistance of human AML to gemtuzumab ozogamicin . PLoS ONE8 ( 1 ), e53518 ( 2013 ).
  • Yachida S , VakianiE , WhiteCMet al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors . Am. J. Surg. Pathol.36 ( 2 ), 173 – 184 ( 2012 ).
  • Marinoni I , KurrerAS , VassellaEet al. Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors . Gastroenterology146 ( 2 ), 453 – 460 ; e455 ( 2014 ).
  • Chen SF , KasajimaA , YazdaniSet al. Clinicopathologic significance of immunostaining of alpha-thalassemia/mental retardation syndrome X-linked protein and death domain-associated protein in neuroendocrine tumors . Hum. Pathol.44 ( 10 ), 2199 – 2203 ( 2013 ).
  • Liu XY , GergesN , KorshunovAet al. Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations . Acta Neuropathologica124 ( 5 ), 615 – 625 ( 2012 ).
  • Lovejoy CA , LiW , ReisenweberSet al. Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway . PLoS Genet.8 ( 7 ), e1002772 ( 2012 ).
  • Qadeer ZA , HarcharikS , Valle-GarciaDet al. Decreased expression of the chromatin remodeler ATRX associates with melanoma progression . J. Invest. Dermatol.134 ( 6 ), 1768 – 1772 ( 2014 ).
  • Athwal RK , WalkiewiczMP , BaekSet al. CENP-A nucleosomes localize to transcription factor hotspots and subtelomeric sites in human cancer cells . Epigenetics Chromatin8 , 2 ( 2015 ).
  • Kapoor A , GoldbergMS , CumberlandLKet al. The histone variant macroH2A suppresses melanoma progression through regulation of CDK8 . Nature468 ( 7327 ), 1105 – 1109 ( 2010 ).
  • Dunleavy EM , RocheD , TagamiHet al. HJURP is a cell-cycle-dependent maintenance and deposition factor of CENP-A at centromeres . Cell137 ( 3 ), 485 – 497 ( 2009 ).
  • Foltz DR , JansenLE , BaileyAOet al. Centromere-specific assembly of CENP-a nucleosomes is mediated by HJURP . Cell137 ( 3 ), 472 – 484 ( 2009 ).
  • Lacoste N , WoolfeA , TachiwanaHet al. Mislocalization of the centromeric histone variant CenH3/CENP-A in human cells depends on the chaperone DAXX . Mol. Cell53 ( 4 ), 631 – 644 ( 2014 ).
  • Jiao Y , ShiC , EdilBHet al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors . Science331 ( 6021 ), 1199 – 1203 ( 2011 ).
  • Jiao Y , KillelaPJ , ReitmanZJet al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas . Oncotarget3 ( 7 ), 709 – 722 ( 2012 ).
  • Schwartzentruber J , KorshunovA , LiuXYet al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma . Nature482 ( 7384 ), 226 – 231 ( 2012 ).
  • Kannan K , InagakiA , SilberJet al. Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma . Oncotarget3 ( 10 ), 1194 – 1203 ( 2012 ).
  • Molenaar JJ , KosterJ , ZwijnenburgDAet al. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes . Nature483 ( 7391 ), 589 – 593 ( 2012 ).
  • Chen X , BahramiA , PappoAet al. Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma . Cell Rep.7 ( 1 ), 104 – 112 ( 2014 ).
  • Elsasser SJ , AllisCD , LewisPW . Cancer. New epigenetic drivers of cancers . Science331 ( 6021 ), 1145 – 1146 ( 2011 ).
  • Fendrich V , WaldmannJ , BartschDK , LangerP . Surgical management of pancreatic endocrine tumors . Nat. Rev. Clin. Oncol.6 ( 7 ), 419 – 428 ( 2009 ).
  • Heaphy CM , De WildeRF , JiaoYet al. Altered telomeres in tumors with ATRX and DAXX mutations . Science333 ( 6041 ), 425 ( 2011 ).
  • Bender S , TangY , LindrothAMet al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas . Cancer Cell24 ( 5 ), 660 – 672 ( 2013 ).
  • Chan KM , FangD , GanHet al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression . Genes Dev.27 ( 9 ), 985 – 990 ( 2013 ).
  • Lewis PW , MullerMM , KoletskyMSet al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma . Science340 ( 6134 ), 857 – 861 ( 2013 ).
  • Cardoso C , TimsitS , VillardL , KhrestchatiskyM , FontesM , ColleauxL . Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein . Hum. Mol. Genet.7 ( 4 ), 679 – 684 ( 1998 ).
  • Funato K , MajorT , LewisPW , AllisCD , TabarV . Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation . Science346 ( 6216 ), 1529 – 1533 ( 2014 ).
  • Astigarraga S , GrossmanR , Diaz-DelfinJ , CaellesC , ParoushZ , JimenezG . A MAPK docking site is critical for downregulation of Capicua by Torso and EGFR RTK signaling . EMBO J.26 ( 3 ), 668 – 677 ( 2007 ).
  • Bettegowda C , AgrawalN , JiaoYet al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma . Science333 ( 6048 ), 1453 – 1455 ( 2011 ).
  • Parsons DW , JonesS , ZhangXet al. An integrated genomic analysis of human glioblastoma multiforme . Science321 ( 5897 ), 1807 – 1812 ( 2008 ).
  • Dang L , WhiteDW , GrossSet al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate . Nature462 ( 7274 ), 739 – 744 ( 2009 ).
  • Sasaki M , KnobbeCB , MungerJCet al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics . Nature488 ( 7413 ), 656 – 659 ( 2012 ).
  • Chowdhury R , YeohKK , TianYMet al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases . EMBO Rep.12 ( 5 ), 463 – 469 ( 2011 ).
  • Sasaki M , KnobbeCB , ItsumiMet al. D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function . Genes Dev.26 ( 18 ), 2038 – 2049 ( 2012 ).
  • Wang G , SaiK , GongF , YangQ , ChenF , LinJ . Mutation of isocitrate dehydrogenase 1 induces glioma cell proliferation via nuclear factor-kappaB activation in a hypoxia-inducible factor 1-alpha dependent manner . Mol. Med. Rep.9 ( 5 ), 1799 – 1805 ( 2014 ).
  • Williams SC , KarajannisMA , ChiribogaL , GolfinosJG , Von DeimlingA , ZagzagD . R132H-mutation of isocitrate dehydrogenase-1 is not sufficient for HIF-1alpha upregulation in adult glioma . Acta Neuropathol.121 ( 2 ), 279 – 281 ( 2011 ).
  • Bower K , NapierCE , ColeSLet al. Loss of wild-type ATRX expression in somatic cell hybrids segregates with activation of alternative lengthening of telomeres . PloS ONE7 ( 11 ), e50062 ( 2012 ).
  • Hastie ND , DempsterM , DunlopMG , ThompsonAM , GreenDK , AllshireRC . Telomere reduction in human colorectal carcinoma and with ageing . Nature346 ( 6287 ), 866 – 868 ( 1990 ).
  • Counter CM , HirteHW , BacchettiS , HarleyCB . Telomerase activity in human ovarian carcinoma . Proc. Natl Acad. Sci. USA91 ( 8 ), 2900 – 2904 ( 1994 ).
  • Killela PJ , ReitmanZJ , JiaoYet al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal . Proc. Natl Acad. Sci. USA110 ( 15 ), 6021 – 6026 ( 2013 ).
  • Cesare AJ , ReddelRR . Alternative lengthening of telomeres: models, mechanisms and implications . Nat. Rev. Genet.11 ( 5 ), 319 – 330 ( 2010 ).
  • Bryan TM , EnglezouA , GuptaJ , BacchettiS , ReddelRR . Telomere elongation in immortal human cells without detectable telomerase activity . EMBO J.14 ( 17 ), 4240 – 4248 ( 1995 ).
  • Ogino H , NakabayashiK , SuzukiMet al. Release of telomeric DNA from chromosomes in immortal human cells lacking telomerase activity . Biochem. Biophys. Res. Commun.248 ( 2 ), 223 – 227 ( 1998 ).
  • Bechter OE , ZouY , WalkerW , WrightWE , ShayJW . Telomeric recombination in mismatch repair deficient human colon cancer cells after telomerase inhibition . Cancer Res.64 ( 10 ), 3444 – 3451 ( 2004 ).
  • Yeager TR , NeumannAA , EnglezouA , HuschtschaLI , NobleJR , ReddelRR . Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body . Cancer Res.59 ( 17 ), 4175 – 4179 ( 1999 ).
  • Conomos D , StutzMD , HillsMet al. Variant repeats are interspersed throughout the telomeres and recruit nuclear receptors in ALT cells . J. Cell Biol.199 ( 6 ), 893 – 906 ( 2012 ).
  • Heaphy CM , SubhawongAP , HongSMet al. Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes . Am. J. Pathol.179 ( 4 ), 1608 – 1615 ( 2011 ).
  • Wu G , LeeWH , ChenPL . NBS1 and TRF1 colocalize at promyelocytic leukemia bodies during late S/G2 phases in immortalized telomerase-negative cells. Implication of NBS1 in alternative lengthening of telomeres . J. Biol. Chem.275 ( 39 ), 30618 – 30622 ( 2000 ).
  • Wu G , JiangX , LeeWH , ChenPL . Assembly of functional ALT-associated promyelocytic leukemia bodies requires Nijmegen Breakage Syndrome 1 . Cancer Res.63 ( 10 ), 2589 – 2595 ( 2003 ).
  • Luciani JJ , DepetrisD , UssonYet al. PML nuclear bodies are highly organised DNA-protein structures with a function in heterochromatin remodelling at the G2 phase . J. Cell Sci.119 ( Pt 12 ), 2518 – 2531 ( 2006 ).
  • Henson JD , HannayJA , MccarthySWet al. A robust assay for alternative lengthening of telomeres in tumors shows the significance of alternative lengthening of telomeres in sarcomas and astrocytomas . Clin. Cancer Res.11 ( 1 ), 217 – 225 ( 2005 ).
  • Costa A , DaidoneMG , DapraiLet al. Telomere maintenance mechanisms in liposarcomas: association with histologic subtypes and disease progression . Cancer Res.66 ( 17 ), 8918 – 8924 ( 2006 ).
  • Perrem K , ColginLM , NeumannAA , YeagerTR , ReddelRR . Coexistence of alternative lengthening of telomeres and telomerase in hTERT-transfected GM847 cells . Mol. Cell. Biol.21 ( 12 ), 3862 – 3875 ( 2001 ).
  • Gibbons RJ , McdowellTL , RamanSet al. Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation . Nat. Genet.24 ( 4 ), 368 – 371 ( 2000 ).
  • Cai J , ChenJ , ZhangWet al. Loss of ATRX, associated with DNA methylation pattern of chromosome end, impacted biological behaviors of astrocytic tumors . Oncotarget6 ( 20 ), 18105 – 18115 ( 2015 ).
  • Noushmehr H , WeisenbergerDJ , DiefesKet al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma . Cancer Cell17 ( 5 ), 510 – 522 ( 2010 ).
  • Sturm D , WittH , HovestadtVet al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma . Cancer Cell22 ( 4 ), 425 – 437 ( 2012 ).
  • Levy MA , FernandesAD , TremblayDC , SeahC , BerubeNG . The SWI/SNF protein ATRX co-regulates pseudoautosomal genes that have translocated to autosomes in the mouse genome . BMC Genomics9 , 468 ( 2008 ).
  • Kernohan KD , VernimmenD , GloorGB , BerubeNG . Analysis of neonatal brain lacking ATRX or MeCP2 reveals changes in nucleosome density, CTCF binding and chromatin looping . Nucleic Acids Res.42 ( 13 ), 8356 – 8368 ( 2014 ).

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