Preface The mitotic checkpoint guards against chromosome missegregation and the production of aneuploid daughter cells. Aneuploidy is a common characteristic of tumor cells and has been proposed for over a century to drive tumor progression. However, recent evidence has revealed that although aneuploidy can increase the potential for cellular transformation, it also acts to antagonize tumorigenesis in certain genetic contexts. A clearer understanding of the tumor suppressive function of aneuploidy may reveal new avenues for anticancer therapy.

Centrioles are conserved microtubule-based organelles that form the core of the centrosome and act as templates for the formation of cilia and flagella. Centrioles have important roles in most microtubule related processes, including motility, cell division and cell signaling. To coordinate these diverse cellular processes, centriole number must be tightly controlled. In cycling cells, one new centriole is formed next to each preexisting centriole in every cell cycle. Advances in imaging, proteomics, structural biology and genome editing have revealed new insights into centriole biogenesis, how centriole numbers are controlled and how alterations in these structures contribute to diseases such as cancer and neurodevelopmental disorders. Moreover, recent work has uncovered the existence of surveillance pathways that limit proliferation of cells with numerical centriole aberrations. Here we discuss recent progress in this field with a focus on signaling pathways and molecular mechanisms.

Binding of STIL activates Plk4, and the subsequent phosphorylation of STIL by Plk4 primes the binding of STIL to SAS6 to promote centriole assembly.

Plk4 phosphorylates itself in trans to prevent accumulation and self-limit kinase activity, which may be important for regulating centriole duplication.

SUMMARY Centrosome amplification is a common feature of human tumors, but whether this is a cause or a consequence of cancer remains unclear. Here, we test the consequence of centrosome amplification by creating mice in which centrosome number can be chronically increased in the absence of additional genetic defects. We show that increasing centrosome number elevated tumor initiation in a mouse model of intestinal neoplasia. Most importantly, we demonstrate that supernumerary centrosomes are sufficient to drive aneuploidy and the development of spontaneous tumors in multiple tissues. Tumors arising from centrosome amplification exhibit frequent mitotic errors and possess complex karyotypes, recapitulating a common feature of human cancer. Together, our data support a direct causal relationship between centrosome amplification, genomic instability and tumor development.

Summary Opposing roles of Aurora kinases and protein phosphatase 1 (PP1) during mitosis have long been suggested. Here we demonstrate that Aurora kinases A and B phosphorylate a single residue on the kinetochore motor CENP-E. PP1 binds CENP-E via a motif overlapping this phosphorylation site and binding is disrupted by Aurora phosphorylation. Phosphorylation of CENP-E by the Auroras is enriched at spindle poles, disrupting binding of PP1 and reducing CENP-E’s affinity for individual microtubules. This phosphorylation is required for CENP-E-mediated towing of initially polar chromosomes toward the cell center. Kinetochores on such chromosomes cannot make subsequent stable attachment to spindle microtubules when dephosphorylation of CENP-E or rebinding of PP1 to CENP-E is blocked. Thus, an Aurora/PP1 phosphorylation switch modulates CENP-E motor activity as an essential feature of chromosome congression from poles and localized PP1 delivery by CENP-E to the outer kinetochore is necessary for stable microtubule capture by those chromosomes.

Cep152, the orthologue of Drosophila Asterless, is a Plk4 target that functions with Plk4 in centriole assembly.

Summary The basic determinant of chromosome inheritance, the centromere, is specified in many eukaryotes by an epigenetic mark. Using gene targeting in human cells and fission yeast, chromatin containing the centromere-specific histone H3 variant CENP-A is demonstrated to be the epigenetic mark that acts through a two-step mechanism to identify, maintain and propagate centromere function indefinitely. Initially, centromere position is replicated and maintained by chromatin assembled with the centromere-targeting domain (CATD) of CENP-A substituted into H3. Subsequently, nucleation of kinetochore assembly onto CATD-containing chromatin is shown to require either CENP-A’s amino- or carboxy-terminal tails for recruitment of inner kinetochore proteins, including stabilizing CENP-B binding to human centromeres or direct recruitment of CENP-C, respectively.