CELL DIVISION AND COHESINOPATHIES
Our research interest is focused on the study of Cell Division and Rare Diseases. We investigate the fundamental mechanisms that control chromosome segregation and mitotic progression- the canonical role of mitotic proteins (1); and on the other hand, we study the functions of a chromosome segregation-associated complex, the cohesin complex, in a human disease such as the Cornelia de Lange Syndrome- the non-canonical role of mitotic proteins (2).
1. THE REGULATION OF THE MITOSIS AND CHROMOSOME SEGREGATION
To study the mechanisms governing mitosis regulation we use mostly the budding yeast as a model organism. The cell cycle in budding yeast is very similar to the cell cycle in humans and is regulated by the same proteins that are conserved through evolution; therefore, it is a perfect model for understanding the cell cycle.
The cell cycle is an ordered series of events happening in eukaryotic cells to grow and divide into two new cells. Basically, cells must complete four major events during the cell cycle: growth (G1 and G2 phases), replicate the DNA (S phase), segregate the chromosome (M phase) and divide (cytokinesis). The cell cyle in budding yeast is very similar to the cell cycle in humans and is regulated by the same proteins that are conserved through evolution.
Proper and timely chromosome segregation is crucial to maintain genome stability and it is at the heart of every mitotic and meiotic cell cycle. Chromosome mis-segregation is tightly linked to tumourigenesis, sterility, mental retardation, miscarriages and birth related defects.
Mitotic exit encompasses an ordered series of events from chromosome segregation during anaphase to completion of cell division by cytokinesis. The budding yeast phosphatase Cdc14 is a major regulator of these events (review in Mocciaro and Schiebel 2010; Meadows and Millar 2015). Two pathways, FEAR (Cdc14 early anaphase release) and MEN (mitotic exit network) activate Cdc14 (Figure 1). However, we do not fully understand the separate and specific regulation of the FEAR and MEN components or how these pathways are coordinated during anaphase. Our group focus in the investigation of those key questions.
2. THE STUDY OF THE COHESIN FUNCTIONS IN RARE DISEASES: THE CORNELIA DE LANGE SYNDROME.
Cornelia de Lange syndrome (CdLS) is a rare disease characterized by growth and mental retardation, craniofacial anomalies and microcephaly. Mutations in five genes that correspond to cohesin-related proteins have been identified in 75% of individuals with clinically diagnosed CdLS: NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Cohesin complex acts as the chromosomal “glue” and is essential for sister chromatids cohesion and their posterior segregation. Recently, numerous observations suggest that cohesin has an important role in the organization of the chromosome architecture. In this project our main objective is to study how the cohesin and Nipbl mutations found in CdLS patients cause the disease phenotypes.
In this research line we aim to get new insight into the cohesin roles in non-diving cells. We expect to further confirm the involvement of cohesin complex in gene expression regulation and how its mutations induce human malignancies as CdLS.