A Molecular View of Kinetochore Assembly and Function

Abstract

Kinetochores are large protein assemblies that connect chromosomes to microtubules of the mitotic and meiotic spindles in order to distribute the replicated genome from a mother cell to its daughters. Kinetochores also control feedback mechanisms responsible for the correction of incorrect microtubule attachments, and for the coordination of chromosome attachment with cell cycle progression. Finally, kinetochores contribute to their own preservation, across generations, at the specific chromosomal loci devoted to host them, the centromeres. They achieve this in most species by exploiting an epigenetic, DNA-sequence-independent mechanism; notable exceptions are budding yeasts where a specific sequence is associated with centromere function. In the last 15 years, extensive progress in the elucidation of the composition of the kinetochore and the identification of various physical and functional modules within its substructure has led to a much deeper molecular understanding of kinetochore organization and the origins of its functional output. Here, we provide a broad summary of this progress, focusing primarily on kinetochores of humans and budding yeast, while highlighting work from other models, and present important unresolved questions for future studies.

Citron kinase – renaissance of a neglected mitotic kinase

“…Complex control and surveillance mechanisms have evolved to ensure the fidelity and robustness of mitotic and meiotic processes. As the chromatin is highly compacted during cell division, these mechanisms rely in large part on post-translational modifications (PTMs) of proteins involved in the assembly and orientation of the mitotic spindle (Prosser and Pelletier, 2017), the attachment and segregation of chromosomes (Musacchio, 2015;Musacchio and Desai, 2017), and the formation and ingression of a cleavage furrow that separates the two daughter cells (Fig. 1) (D'Avino et al, 2015).…”

Kinetochores accelerate or delay APC/C activation by directing Cdc20 to opposing fates

“…Cdc20 is also central to the spindle assembly checkpoint, a mechanism that promotes accurate chromosome segregation by delaying anaphase onset until all of the kinetochores, the microtubule-binding machines of mitotic chromosomes (Cheeseman 2014;Musacchio and Desai 2017), have established attachments to spindle microtubules. At unattached kinetochores, the spindle checkpoint pathway-comprised of the Bub1/Bub3 complex, the Mad1/Mad2 complex, Mad3 (known as BubR1 in vertebrates and Drosophila), and the kinases Mps1 and Plk1-generates a diffusible complex containing Cdc20 that inhibits the APC/C (Lara- Gonzalez et al 2012;Musacchio 2015).…”

Molecular Structures of Yeast Kinetochore Subcomplexes and Their Roles in Chromosome Segregation

“…These proteins in turn direct deposition of a single, centromere-specific nucleosome (Meluh et al 1998). The "parts list" for the kinetochores that then assemble on the so-called "point centromeres" of budding yeast now includes more than 50 distinct gene products (depending on how one chooses to define a "part"), most of them associated into distinct, multiprotein complexes (De Wulf et al 2003;Musacchio and Desai 2017). Conservation of many of these complexes among eukaryotes has reinforced the view that a budding-yeast kinetochore represents a simplified module of the kinetochores distributed over much longer centromeres in other organisms (Fig.…”