Fernando Monje-Casas

Both the spindle microtubule-organizing centers and the nuclear pore complexes (NPCs) are convoluted structures where many signaling pathways converge to coordinate key events during cell division. Interestingly, despite their distinct molecular conformation and overall functions, these structures share common components and collaborate in the regulation of essential processes. We have established a new link between microtubule-organizing centers and nuclear pores in budding yeast by unveiling an interaction between the Bfa1/Bub2 complex, a mitotic exit inhibitor that localizes on the spindle pole bodies, and the Nup159 nucleoporin. Bfa1/Bub2 association with Nup159 is reduced in metaphase to not interfere with proper spindle positioning. However, their interaction is stimulated in anaphase and assists the Nup159-dependent autophagy pathway. The asymmetric localization of Bfa1/Bub2 during mitosis raises the possibility that its interaction with Nup159 could differentially promote Nup159-mediated autophagic processes, which might be relevant for the maintenance of the replicative lifespan.

The microtubules that form the mitotic spindle originate from microtubule-organizing centers (MTOCs) located at either pole. After duplication, spindle MTOCs can be differentially inherited during asymmetric cell division in organisms ranging from yeast to humans. Problems with establishing predetermined spindle MTOC inheritance patterns during stem cell division have been associated with accelerated cellular aging and the development of both cancer and neurodegenerative disorders. Here, we expand the repertoire of functions Polo-like kinase family members fulfill in regulating pivotal cell cycle processes. We demonstrate that the Plk1 homolog Cdc5 acts as a molecular timer that facilitates the timely and sequential recruitment of two key determinants of spindle MTOCs distribution, that is the γ-tubulin complex receptor Spc72 and the protein Kar9, and establishes the fate of these structures, safeguarding their asymmetric inheritance during Saccharomyces cerevisiae mitosis.

The spindle constitutes the cellular machinery that enables the segregation of the chromosomes during eukaryotic cell division. The microtubules that form this fascinating and complex genome distribution system emanate from specialized structures located at both its poles and known as microtubule-organizing centers (MTOCs). Beyond their structural function, the spindle MTOCs play fundamental roles in cell cycle control, the activation and functionality of the mitotic checkpoints and during cellular aging. This review highlights the pivotal importance of spindle-associated MTOCs in multiple cellular processes and their central role as key regulatory hubs where diverse intracellular signals are integrated and coordinated to ensure the successful completion of cell division and the maintenance of the replicative lifespan.

Although cell division is usually portrayed as an equitable process by which a progenitor cell originates two identical daughter cells, there are multiple examples of asymmetric divisions that generate two cells that differ in their content, morphology and/or proliferative potential. The capacity of the cells to generate asymmetry during their division is of paramount biological relevance, playing essential roles during embryonic development, cellular regeneration and tissue morphogenesis. Problems with the proper establishment of asymmetry and polarity during cell division can give rise to cancer and neurodevelopmental disorders, as well as to also accelerate cellular aging. Interestingly, the microtubule organizing centers that orchestrate the formation of the mitotic spindle have been described among the cellular structures that can be differentially allocated during asymmetric cell divisions. This mini-review focuses on recent research from our group and others uncovering a role for the non-random distribution of the spindle-associated microtubule organizing centers in the differential distribution of aging factors during asymmetric mitoses and therefore in the maintenance of the replicative lifespan of the cells.

In order to preserve genome integrity and their ploidy, cells must ensure that the duplicated genome has been faithfully replicated and evenly distributed before they complete their division by mitosis. To this end, cells have developed highly elaborated checkpoints that halt mitotic progression when problems in DNA integrity or chromosome segregation arise, providing them with time to fix these issues before advancing further into the cell cycle. Remarkably, exit from mitosis constitutes a key cell cycle transition that is targeted by the main mitotic checkpoints, despite these surveillance mechanisms being activated by specific intracellular signals and acting at different stages of cell division. Focusing primarily on research carried out using Saccharomyces cerevisiae as a model organism, the aim of this review is to provide a general overview of the molecular mechanisms by which the major cell cycle checkpoints control mitotic exit and to highlight the importance of the proper regulation of this process for the maintenance of genome stability during the distribution of the duplicated chromosomes between the dividing cells.

The Cdc14 phosphatase is a key regulator of mitosis in the budding yeast Saccharomyces cerevisiae. Cdc14 was initially described as playing an essential role in the control of cell cycle progression by promoting mitotic exit on the basis of its capacity to counteract the activity of the cyclin-dependent kinase Cdc28/Cdk1. A compiling body of evidence, however, has later demonstrated that this phosphatase plays other multiple roles in the regulation of mitosis at different cell cycle stages. Here, we summarize our current knowledge about the pivotal role of Cdc14 in cell cycle control, with a special focus in the most recently uncovered functions of the phosphatase.

The differential distribution of the microtubule-organizing centres (MTOCs) that orchestrate spindle formation during cell division is a fascinating phenomenon originally described in Saccharomyces cerevisiae and later found to be conserved during stem cell divisions in organisms ranging from Drosophila to humans. Whether predetermined MTOC inheritance patterns fulfil any biological function is however unknown. Using a genetically designed S. cerevisiae strain that displays a constitutively inverted MTOC fate, we demonstrate that the asymmetric segregation of these structures is critical to ensure normal levels of the Sir2 sirtuin and correct localization of the mitochondrial inheritance regulator Mfb1, and therefore to properly distribute functional mitochondria and protein aggregates between the mother and daughter cells. Consequently, interfering with this process severely accelerates cellular ageing.