title: ATRX represses alternative lengthening of telomeres.
abstract: The unlimited proliferation of cancer cells requires a mechanism to prevent telomere shortening. Alternative Lengthening of Telomeres (ALT) is an homologous recombination-mediated mechanism of telomere elongation used in tumors, including osteosarcomas, soft tissue sarcoma subtypes, and glial brain tumors. Mutations in the ATRX/DAXX chromatin remodeling complex have been reported in tumors and cell lines that use the ALT mechanism, suggesting that ATRX may be an ALT repressor. We show here that knockout or knockdown of ATRX in mortal cells or immortal telomerase-positive cells is insufficient to activate ALT. Notably, however, in SV40-transformed mortal fibroblasts ATRX loss results in either a significant increase in the proportion of cell lines activating ALT (instead of telomerase) or in a significant decrease in the time prior to ALT activation. These data indicate that loss of ATRX function cooperates with one or more as-yet unidentified genetic or epigenetic alterations to activate ALT. Moreover, transient ATRX expression in ALT-positive/ATRX-negative cells represses ALT activity. These data provide the first direct, functional evidence that ATRX represses ALT.
authors.affiliation: Cancer Research Unit, Children's Medical Research Institute, The University of Sydney, Westmead, NSW, Australia.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Napier
authors.affiliation: Cancer Research Unit, Children's Medical Research Institute, The University of Sydney, Westmead, NSW, Australia.
authors.forename: Lily I
authors.initials: LI
authors.lastname: Huschtscha
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Harvey
authors.affiliation: Cancer Research Unit, Children's Medical Research Institute, The University of Sydney, Westmead, NSW, Australia.
authors.forename: Kylie
authors.initials: K
authors.lastname: Bower
authors.affiliation: Cancer Research Unit, Children's Medical Research Institute, The University of Sydney, Westmead, NSW, Australia.
authors.forename: Jane R
authors.initials: JR
authors.lastname: Noble
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hendrickson
authors.affiliation: Cancer Research Unit, Children's Medical Research Institute, The University of Sydney, Westmead, NSW, Australia.|Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Roger R
authors.initials: RR
authors.lastname: Reddel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D002461:Cell Line, Transformed; D056970:Co-Repressor Proteins; D004265:DNA Helicases / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008297:Male; D018832:Molecular Chaperones; D009369:Neoplasms / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D013539:Simian virus 40 / Q000235:genetics; D016615:Telomere / Q000235:genetics*; D059505:Telomere Homeostasis / Q000235:genetics*; D000075924:X-linked Nuclear Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: ALT; ATRX; immortalization; telomere