Inositol Pyrophosphate Kinase Asp1 Modulates Chromosome Segregation Fidelity and Spindle Function in Schizosaccharomyces pombe

• Published in: Molecular and cellular biology 2016-12, Vol.36 (24), p.3128-3140
• Main Authors: Topolski, Boris, Jakopec, Visnja, Künzel, Natascha A., Fleig, Ursula
• Format: Article
• Language: English
• Subjects: Chromosome Segregation; Chromosomes, Fungal - genetics; Cytoskeletal Proteins - chemistry; Cytoskeletal Proteins - metabolism; Inositol Phosphates - metabolism; Kinetochores - metabolism; Microtubules - metabolism; Mitosis; Protein Domains; Schizosaccharomyces - genetics; Schizosaccharomyces - metabolism; Schizosaccharomyces pombe; Schizosaccharomyces pombe Proteins - chemistry; Schizosaccharomyces pombe Proteins - metabolism; Spindle Apparatus - metabolism; Spotlight
• ISSN: 1098-5549; 0270-7306; 1098-5549
• DOI: 10.1128/MCB.00330-16

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.