The Eukaryotic Cell Cycle team studies the internal mechanisms that control the proliferation of eukaryotic cells and orchestrate the different steps of the cell cycle. More precisely, the group is interested in the mechanisms that (1) regulate cyclin activity as a consequence of internal signals for cell cycle entry and (2) coordinate DNA replication and chromosome segregation by SMC proteins.
Cells adapt their size to both intrinsic and extrinsic demands and, among them, those that stem from growth and proliferation rates are crucial to keep a proper ploidy/mass ratio as a key condition for genome integrity. Cyclin Cln3, the most upstream activator of Start in budding yeast, is retained at the endoplasmic reticulum in early G1 and released by specific chaperones in late G1 to initiate the cell cycle. On one hand, these chaperones are rate-limiting for release of Cln3 and cell cycle entry and, on the other hand, they are required for key biosynthetic processes. The competition for specialized chaperones between growth and cycle machineries could gauge biosynthetic rates and set a critical size threshold at Start. We are currently working in the identification of the protein complex that retains the G1 cyclin in the ER and how this complex is regulated during release in late G1. A theoretical model to describe cell cycle entry as a function of this retention-release mechanism at the ER is being developed. Since we have found that cyclin D1 is retained at a cytoplasm structure in MEFs arrested in G1, we are also trying to pinpoint the proteins and characterize the mechanisms that exert this retention, aiming to test its functional relevance in development and tumorogenesis.
Coordination of replication and segregation of all chromosomes is essential for proper inheritance of the genetic material. Three essential complexes of the Structural Maintenance of Chromosomes (SMC) family, cohesin, condensin and the Smc5/6 complex, play key roles in maintaining genome integrity during the cell cycle. Our work has established that the Smc5/6 complex is involved in the segregation of specific chromosomal regions, and smc5/6 mutants suffer from aberrant recombination and from defects in completing rDNA replication before anaphase. Since some smc mutants are also highly sensitive to genotoxic agents, we are studying the role of SMC complexes in the replication of a damaged DNA template and the regulation of SMC proteins by the SUMO pathway. Besides, we are working on cellular models to confirm or exclude the postulated existence of a "DNA replication completion checkpoint".
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While harmonization of growth and cell cycle entry rates determines efficient ploidy/mass ratios, coordination of chromosome replication and segregation is key for genome stability, being both equally crucial independently of cell fate and function.