title: Rapid induction of alternative lengthening of telomeres by depletion of the histone chaperone ASF1.
abstract: The mechanism of activation of the alternative lengthening of telomeres (ALT) pathway of mammalian chromosome-end maintenance has been unclear. We have now discovered that co-depletion of the histone chaperones ASF1a and ASF1b in human cells induced all hallmarks of ALT in both primary and cancer cells. These included the formation of ALT-associated PML (promyelocytic leukemia) bodies (APBs), the presence of extrachromosomal telomeric DNA species, an elevated frequency of telomeric sister chromatid exchanges (t-SCE) events and intertelomeric exchange of an integrated tag. The induction of ALT characteristics in this setting led to the simultaneous suppression of telomerase. We determined that ALT induction is positively regulated by the proteins RAD17 and BLM and negatively regulated by EXO1 and DNA2. The induction of ALT phenotypes as a consequence of ASF1 depletion strongly supports the hypothesis that ALT is a consequence of histone management dysfunction.
authors.affiliation: Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: O'Sullivan
authors.affiliation: Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Nausica
authors.initials: N
authors.lastname: Arnoult
authors.affiliation: Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Lackner
authors.affiliation: Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Liana
authors.initials: L
authors.lastname: Oganesian
authors.affiliation: Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Candy
authors.initials: C
authors.lastname: Haggblom
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris, France. [2] Centre National de la Recherche Scientifique, Paris, France. [3].
authors.forename: Armelle
authors.initials: A
authors.lastname: Corpet
authors.affiliation: 1] Institut Curie, Centre de Recherche, Paris, France. [2] Centre National de la Recherche Scientifique, Paris, France.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Almouzni
authors.affiliation: Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Karlseder
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D004261:DNA Replication; D005786:Gene Expression Regulation; D006801:Humans; D007700:Kinetics; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D059505:Telomere Homeostasis / Q000235:genetics*
chemical_list: C491641:ASF1A protein, human; C491640:ASF1B protein, human; D018797:Cell Cycle Proteins; D018832:Molecular Chaperones; C509186:TERT protein, human; D019098:Telomerase