title: Loss of ATRX Suppresses Resolution of Telomere Cohesion to Control Recombination in ALT Cancer Cells.
abstract: The chromatin-remodeler ATRX is frequently lost in cancer cells that use ALT (alternative lengthening of telomeres) for telomere maintenance, but its function in telomere recombination is unknown. Here we show that loss of ATRX suppresses the timely resolution of sister telomere cohesion that normally occurs prior to mitosis. In the absence of ATRX, the histone variant macroH2A1.1 binds to the poly(ADP-ribose) polymerase tankyrase 1, preventing it from localizing to telomeres and resolving cohesion. The resulting persistent telomere cohesion promotes recombination between sister telomeres, while it suppresses inappropriate recombination between non-sisters. Forced resolution of sister telomere cohesion induces excessive recombination between non-homologs, genomic instability, and impaired cell growth, indicating the ATRX-macroH2A1.1-tankyrase axis as a potential therapeutic target in ALT tumors.
authors.affiliation: Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, Department of Pathology, NYU Langone Medical Center and School of Medicine, New York, NY 10016, USA.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Ramamoorthy
authors.affiliation: Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, Department of Pathology, NYU Langone Medical Center and School of Medicine, New York, NY 10016, USA. Electronic address: susan.smith@med.nyu.edu.
authors.forename: Susan
authors.initials: S
authors.lastname: Smith
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000235:genetics; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000235:genetics*; D059505:Telomere Homeostasis / Q000235:genetics; D000075924:X-linked Nuclear Protein
chemical_list: D006657:Histones; D009687:Nuclear Proteins; D011065:Poly(ADP-ribose) Polymerases; D019098:Telomerase; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein