title: Inositol Pyrophosphate Kinase Asp1 Modulates Chromosome Segregation Fidelity and Spindle Function in Schizosaccharomyces pombe.
abstract: Chromosome transmission fidelity during mitosis is of critical importance for the fitness of an organism, as mistakes will lead to aneuploidy, which has a causative role in numerous severe diseases. Proper segregation of chromosomes depends on interdependent processes at the microtubule-kinetochore interface and the spindle assembly checkpoint. Here we report the discovery of a new element essential for chromosome transmission fidelity that implicates inositol pyrophosphates (IPPs) as playing a key role in this process. The protein is Asp1, the Schizosaccharomyces pombe member of the highly conserved Vip1 family. Vip1 enzymes are bifunctional: they consist of an IPP-generating kinase domain and a pyrophosphatase domain that uses such IPPs as substrates. We show that Asp1 kinase function is required for bipolar spindle formation. The absence of Asp1-generated IPPs resulted in errors in sister chromatid biorientation, a prolonged checkpoint-controlled delay of anaphase onset, and chromosome missegregation. Remarkably, expression of Asp1 variants that generated higher-than-wild-type levels of IPPs led to a faster-than-wild-type entry into anaphase A without an increase in chromosome missegregation. In fact, the chromosome transmission fidelity of a nonessential chromosome was enhanced with increased cellular IPPs. Thus, we identified an element that optimized the wild-type chromosome transmission process.
authors.affiliation: Institut für Funktionelle Genomforschung der Mikroorganismen, Eukaryotische Mikrobiologie, Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Topolski
authors.affiliation: Institut für Funktionelle Genomforschung der Mikroorganismen, Eukaryotische Mikrobiologie, Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Visnja
authors.initials: V
authors.lastname: Jakopec
authors.affiliation: Institut für Funktionelle Genomforschung der Mikroorganismen, Eukaryotische Mikrobiologie, Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Natascha A
authors.initials: NA
authors.lastname: Künzel
authors.affiliation: Institut für Funktionelle Genomforschung der Mikroorganismen, Eukaryotische Mikrobiologie, Heinrich-Heine-Universität, Düsseldorf, Germany fleigu@hhu.de.
authors.forename: Ursula
authors.initials: U
authors.lastname: Fleig
mesh_terms: D020090:Chromosome Segregation; D015825:Chromosomes, Fungal / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism*; D007295:Inositol Phosphates / Q000378:metabolism; D018386:Kinetochores / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D064251:Multifunctional Enzymes; D000072417:Protein Domains; D011755:Pyrophosphatases; D012568:Schizosaccharomyces / Q000235:genetics* / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry / Q000378:metabolism*; D008941:Spindle Apparatus / Q000378:metabolism*
chemical_list: C121265:Asp1 protein, S pombe; D003598:Cytoskeletal Proteins; D007295:Inositol Phosphates; D064251:Multifunctional Enzymes; D029702:Schizosaccharomyces pombe Proteins; D011755:Pyrophosphatases