Cell division control

Every time a cell divides, it must accurately duplicate and distribute its genetic material. Defects in chromosome segregation can lead to genome instability and aneuploidy, which are linked to cancer and numerous genetic disorders.  Using the budding yeast Saccharomyces cerevisiae and human cells as complementary model systems, we combine genetics, cell biology, microscopy, and biochemical approaches to address fundamental questions in genome biology and cell division. In this way, our research seeks to understand how cells coordinate chromosome segregation with cell-cycle progression and how genome integrity and proper ploidy are safeguarded during cell division. Additionally, we are interested in exploring how cells can generate polarity during their division and, particularly, how the same molecular machinery responsible for genome segregation can be used to establish cellular asymmetry.

Our research is organized around two main research areas.

1.- Mechanisms that ensure faithful genome segregation

Maintaining genome integrity and proper ploidy is essential for the survival and fitness of both unicellular and multicellular organisms. A central role in this process is played by the spindle, a highly dynamic bipolar array of microtubules that captures and segregates chromosomes during cell division. The accurate transmission of genetic information also relies on a series of checkpoints that monitor the completion of critical cellular events and delay cell division until potential defects have been resolved. These surveillance mechanisms include the DNA damage checkpoint (DDC), which detects and responds to DNA lesions, and the spindle assembly checkpoint (SAC), which ensures that chromosomes are properly attached to the mitotic spindle before segregation. In addition, cells undergoing asymmetric division must also monitor spindle orientation. This particular type of surveillance mechanism was first described in S. cerevisiae, where the spindle position checkpoint (SPOC) prevents exit from mitosis when the spindle fails to align correctly with the mother–daughter axis. A major aim of our laboratory is to understand how these checkpoint pathways are activated, regulated, and integrated to guarantee faithful genome transmission. 

Interestingly, although the DDC, SAC, and SPOC respond to distinct cellular cues and mainly operate at different stages of mitosis, a common feature of these checkpoints is that they inhibit mitotic exit. This observation highlights exit from mitosis as a critical target of regulatory mechanisms that preserve genome integrity. Accordingly, a central goal of our research is to elucidate the signaling pathways that govern mitotic exit and to understand how the different checkpoints regulate these signalling networks to delay the completion of mitosis when genome integrity, chromosome segregation, or spindle positioning is compromised.

Finally, another important focus of our research in this area is Aurora B kinase, a master regulator of chromosome segregation. Aurora B plays an essential role in correcting erroneous chromosome–microtubule attachments and ensuring the proper bi-orientation of sister chromatids before anaphase onset. Accordingly, loss of Aurora B activity causes severe chromosome segregation defects, aneuploidy, and cell lethality. Notably, increased Aurora B levels can also promote aneuploidy and have been associated with several types of cancer. Our work seeks to define how Aurora B activity is regulated throughout the cell cycle, how this kinase collaborates with checkpoint pathways to maintain chromosome segregation fidelity, and how perturbations in Aurora B levels contribute to genome instability and disease.

2.- Generation of asymmetry during cell division

Although cell division is often portrayed as a process that generates two identical daughter cells, many divisions are intrinsically asymmetric. In higher eukaryotes, stem cells provide one of the most important examples of asymmetric cell division. By generating one cell that retains stem cell identity and another that undergoes differentiation, these cells maintain the balance between self-renewal and tissue regeneration. A reduction in the stem cell population can lead to tissue disorganization, degeneration and aging. Conversely, an excessive number of stem cells can promote tissue hyperplasia and contribute to cancer development. Understanding how asymmetry is generated and maintained during cell division is therefore a fundamental scientific challenge. The budding yeast S. cerevisiae provides an exceptional model system for addressing this question, since every cell division in this organism is inherently asymmetric.

An asymmetric cell division requires the establishment of a predetermined polarity axis, followed by the orientation of the mitotic spindle along this axis and perpendicular to the division plane. By aligning with the polarity axis, the spindle is optimally positioned to assist the asymmetric distribution of cellular components during cell division. A central goal of our research is to understand how cells can repurpose the molecular machinery responsible for chromosome segregation to establish polarity and generate asymmetry during cell division. In particular, we are interested in the role played by the microtubule-organizing centers (MTOCs), the structures from which the spindle microtubules nucleate and that locate at both spindle poles. In human cells, the main spindle MTOCs are known as centrosomes, whereas in budding yeast they are called spindle pole bodies (SPBs). Notably, the selective association of molecules and organelles with only one spindle MTOCs enables their differential distribution as the spindle elongates and only one MTOC enters the daughter cell. 

Intriguingly, spindle MTOCs can themselves be asymmetrically inherited during mitosis. This fascinating phenomenon was first described in S. cerevisiae, and was later shown to be evolutionary conserved. Research in our laboratory demonstrated that asymmetric inheritance of the SPBs is required for yeast cells to maintain their full replicative lifespan, revealing an unexpected connection between spindle asymmetry and cellular aging. By investigating how spindle-associated mechanisms contribute to the establishment of polarity during asymmetric cell divisions, we aim to uncover fundamental principles governing these processes and gain new insights into age-related human diseases, including cancer and neurodegenerative disorders.

 

Funding and institutional support: