Cell cycle regulation by complex nanomachines

The cell cycle is the essential biological process where one cell replicates its genome and segregates the resulting two copies into the daughter cells during mitosis. Several aspects of this process have fascinated humans since the nineteenth century. Today, the cell cycle is exhaustively investigated because of its profound connections with human diseases and cancer. At the heart of the molecular network controlling the cell cycle, we find the cyclin-dependent kinases (CDKs) acting as an oscillator to impose an orderly and highly regulated progression through the different cell cycle phases. This oscillator integrates both internal and external signals via a multitude of signalling pathways involving posttranslational modifications including phosphorylation, protein ubiquitination and mechanisms of transcriptional regulation. These tasks are specifically performed by multi-subunit complexes, which are intensively studied both biochemically and structurally with the aim to unveil mechanistic insights into their molecular function. The scope of this review is to summarise the structural biology of the cell cycle machinery, with specific focus on the core cell cycle machinery involving the CDK-cyclin oscillator. We highlight the contribution of cryo-electron microscopy, which has started to revolutionise our understanding of the molecular function and dynamics of the key players of the cell cycle.