title: INPP5E Preserves Genomic Stability through Regulation of Mitosis.
abstract: The partially understood phosphoinositide signaling cascade regulates multiple aspects of cellular metabolism. Previous studies revealed that INPP5E, the inositol polyphosphate-5-phosphatase that is mutated in the developmental disorders Joubert and MORM syndromes, is essential for the function of the primary cilium and maintenance of phosphoinositide balance in nondividing cells. Here, we report that INPP5E further contributes to cellular homeostasis by regulating cell division. We found that silencing or genetic knockout ofINPP5Ein human and murine cells impairs the spindle assembly checkpoint, centrosome and spindle function, and maintenance of chromosomal integrity. Consistent with a cell cycle regulatory role, we found that INPP5E expression is cell cycle dependent, peaking at mitotic entry. INPP5E localizes to centrosomes, chromosomes, and kinetochores in early mitosis and shuttles to the midzone spindle at mitotic exit. Our findings identify the previously unknown, essential role of INPP5E in mitosis and prevention of aneuploidy, providing a new perspective on the function of this phosphoinositide phosphatase in health and development.
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Sierra Potchanant
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Cerabona
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Zahi Abdul
authors.initials: ZA
authors.lastname: Sater
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Zejin
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Gehlhausen
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA gnalepa@iu.edu.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.|Division of Pediatric Hematology-Oncology, Riley Hospital for Children, Indianapolis, Indiana, USA.
authors.forename: Grzegorz
authors.identifier: http://orcid.org/0000-0002-5779-9103
authors.initials: G
authors.lastname: Nalepa
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D042822:Genomic Instability; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D007399:Interphase; D059566:M Phase Cell Cycle Checkpoints; D051379:Mice; D008938:Mitosis / Q000235:genetics*; D008954:Models, Biological; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D021381:Protein Transport; D013347:Subcellular Fractions / Q000378:metabolism; D013379:Substrate Specificity; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D019269:Phosphatidylinositol 4,5-Diphosphate; D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases
keywords: INPP5E; aneuploidy; cell cycle; centrosomes; mitosis; spindle assembly checkpoint