title: Bub1 maintains centromeric cohesion by activation of the spindle checkpoint.
abstract: Bub1 is a component of the spindle assembly checkpoint (SAC), a surveillance mechanism that ensures genome stability by delaying anaphase until all the chromosomes are stably attached to spindle microtubules via their kinetochores. To define Bub1's role in chromosome segregation, embryogenesis, and tissue homeostasis, we generated a mouse strain in which BUB1 can be inactivated by administration of tamoxifen, thereby bypassing the preimplantation lethality associated with the Bub1 null phenotype. We show that Bub1 is essential for postimplantation embryogenesis and proliferation of primary embryonic fibroblasts. Bub1 inactivation in adult males inhibits proliferation in seminiferous tubules, reducing sperm production and causing infertility. In culture, Bub1-deficient fibroblasts fail to align their chromosomes or sustain SAC function, yielding a highly aberrant mitosis that prevents further cell divisions. Centromeres in Bub1-deficient cells also separate prematurely; however, we show that this is a consequence of SAC dysfunction rather than a direct role for Bub1 in protecting centromeric cohesion.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Perera
authors.forename: Valerie
authors.initials: V
authors.lastname: Tilston
authors.forename: Jane A
authors.initials: JA
authors.lastname: Hopwood
authors.forename: Marco
authors.initials: M
authors.lastname: Barchi
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Boot-Handford
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Taylor
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002503:Centromere / Q000502:physiology*; D020090:Chromosome Segregation; D020964:Embryo Loss; D004622:Embryo, Mammalian / Q000166:cytology / Q000502:physiology; D047108:Embryonic Development; D005347:Fibroblasts / Q000502:physiology; D007248:Infertility, Male / Q000235:genetics*; D018386:Kinetochores / Q000502:physiology; D008297:Male; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D013091:Spermatogenesis / Q000502:physiology*; D008941:Spindle Apparatus / Q000502:physiology*
chemical_list: C584281:Bub1 protein, mouse; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases