On the Regulation of Mitosis by the Kinetochore, a Macromolecular Complex and Organising Hub of Eukaryotic Organisms.

Abstract

The kinetochore is the multiprotein complex of eukaryotic organisms that is assembled on mitotic or meiotic centromeres to connect centromeric DNA with microtubules. Its function involves the coordinated action of more than 100 different proteins. The kinetochore acts as an organiser hub that establishes physical connections with microtubules and centromere-associated proteins and recruits central protein components of the spindle assembly checkpoint (SAC), an evolutionarily conserved surveillance mechanism of eukaryotic organisms that detects unattached kinetochores and destabilises incorrect kinetochore-microtubule attachments. The molecular communication between the kinetochore and the SAC is highly dynamic and tightly regulated to ensure that cells can progress towards anaphase until each chromosome is properly bi-oriented on the mitotic spindle. This is achieved through an interplay of highly cooperative interactions and concerted phosphorylation/dephosphorylation events that are organised in time and space.This contribution discusses our current understanding of the function, structure and regulation of the kinetochore, in particular, how its communication with the SAC results in the amplification of specific signals to exquisitely control the eukaryotic cell cycle. This contribution also addresses recent advances in machine learning approaches, cell imaging and proteomics techniques that have enhanced our understanding of the molecular mechanisms that ensure the high fidelity and timely segregation of the genetic material every time a cell divides as well as the current challenges in the study of this fascinating molecular machine.