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 fasterthan-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. In eukaryotes, the faithful transmission of genetic information from one generation to the next is tightly controlled. Genome instability generally has a strong negative impact on the fitness of an organism. Decreased chromosome segregation fidelity during cell division will give rise to cell progeny which have lost or gained chromosomes. Aneuploidy is a distinguishing feature of many types of cancer and neurological diseases and has been implicated as an important factor in the aging process (1, 2). It is a poorly understood paradox that genome plasticity can also be advantageous for the propagation of cells or an organism. Aneuploid tumor cells have a proliferative advantage, and large-scale chromosome changes are a common feature of human-pathogenic fungi such as Candida. In the latter case, these alterations facilitate an adaption to the environment resulting in increased survival (3).Chromosome segregation is a precise process: in model yeasts such as the fission yeast Schizosaccharomyces pombe where in vivo chromosome loss rates can be determined easily, it is approximately 0.01% (reviewed in reference 4). Chromosome transmission fidelity depends on the formation and function of the bipolar spindle, the multicomponent kinetochore complex assembled on centromeric chromatin, and the correct connections between these two structures. Biorientation of sister chromatids requires the binding of plus ends of spindle microtubules (MTs) to attachment sites on the kinetochore in such a way that sisters are bound to MTs polymerized from opposing spindle poles. Incorrect attachments are common and are corrected by the Aur...
Chromosome segregation is powered by the kinetochore, a large macromolecular structure assembled on centromeric chromatin. Attachment of sister chromatids to microtubules is mediated by the highly conserved tripartite KMN (acronym for KNL-1-Mis12-Ndc80) kinetochore network. In the fission yeast Schizosaccharomyces pombe, the equivalent complex is called NMS (Ndc80-MIND-Spc7). Here, we show that not all components of the NMS complex had been identified previously. A 10th NMS component exists, the essential Sos7 protein, which is a genetic and physical interaction partner of Spc7. The analysis of sos7 kinetochore-null mutant yeast strains demonstrated that Sos7 is central to NMS function. In particular, Sos7 is required for kinetochore targeting of Spc7 as well as components of the MIND complex. sos7 mutant strains show severe chromosome missegregation phenotypes and have compromised microtubule-kinetochore interactions. Sos7 is the founding member of a functionally conserved fungal kinetochore family not present in the point centromere carrying Saccharomycotina clusters, suggesting that the new Sos7 family might be a signature motif of fungi with regional centromeres.T he faithful transmission of eukaryotic chromosomes to the progeny is a complex process that requires coordinated protein interactions at the kinetochore-microtubule interface. The erosion of chromosome segregation fidelity leading to the loss/gain of chromosomes is of great medical relevance, as aneuploidy has been implicated to have a causative role in a number of diseases (1,38,68). The proper partitioning of sister chromatids in mitotis is mediated via direct contact of spindle microtubules with components of the outer kinetochore. Kinetochores are macromolecular structures assembled on the chromosomal centromere region. Apart from providing mechanical attachment sites, these organelles generate the spindle checkpoint signaling that ascertains proper sister chromatid biorientation before anaphase onset (44). Although kinetochores are very complex structures and the number of kinetochore proteins identified is still increasing, the direct interaction with spindle fibers is mediated largely by a highly conserved protein network called the KMN complex in higher eucaryotes and the NMS complex in the fission yeast Schizosaccharomyces pombe (2, 37, 47). The KMN-NMS network is composed of 3 subcomplexes: the Ndc80 complex and the MINDMis12 complex, each comprising 4 components, and a protein called KNL-1 in Caenorhabditis elegans, Blinkin-hSpc105 in vertebrates, Spc105 in Saccharomyces cerevisiae and Drosophila, and Spc7 in S. pombe (59,67,74). In addition, budding yeast Spc105 forms a subcomplex with the Kre28 protein, Blinkin binds metazoan Zwint via its C-terminal end, and KNL-1 interacts with 29,30,[46][47][48]. The mitotic functions of Kre28 and KBP-5 have yet to be analyzed, whereas the Zwint protein is required for kinetochore residency of the mitotic checkpoint relevant RZZ (Rod-Zw10-Zwilch) complex (10,65,70). It has been suggested that Kre28 ...
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