The four causes: the functional architecture of centromeres and kinetochores

Kinetochores are molecular machines that power chromosome segregation during the mitotic and meiotic cell divisions of all eukaryotes. Aristotle explains how we think we have knowledge of a thing only when we have grasped its cause. The four causes correspond to questions that one must ask to gain understanding of natural phenomena - which in our case is the Kinetochore: 1) What are the constituent parts? 2) How does it assemble? 3) What is the structure and arrangement? and 4) What is the function? Here we outline the current blueprint for the assembly of a kinetochore, how functions are mapped onto this architecture and how this is shaped by the underlying pericentromeric chromatin. This is possible because an almost complete parts list of the kinetochore is now available alongside recent advances using in vitro reconstitution, structural biology and genomics. In many organisms each kinetochore binds to multiple microtubules and we propose a model for how this ensemble-level architecture is organised, drawing on key insights from the simple “one microtubule-one kinetochore” setup in budding yeast and innovations that enable meiotic chromosome segregation.