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.

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Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00330-16.

ACKNOWLEDGMENTS

We thank Jennifer Pöhlmann for help with Fig. S1 in the supplemental material and Robin Allshire, Kathleen Gould, Keith Gull, Iain Hagan, Silke Hauf, Alison Pidoux, Shelley Sazer, Takashi Toda, Mitsuhiro Yanagida, and the Yeast Genetic Resource Centre for the gifts of reagents used in this work. We are grateful to Shelley Sazer for critical input and careful reading of the manuscript and to the Center for Advanced Imaging (CAi) at the Heinrich-Heine-University, Düsseldorf, for help with microscopic analysis.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sector.

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Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sector.