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Research overview

Dr Claudio Alfieri, Molecular Mechanisms of Cell Cycle Regulation

The cell cycle is the fundamental biological process where the cell coordinates chromosome replication and segregation with cell growth and division. In response to internal/external cues individual metazoan cells can exit from the cell cycle. Cell cycle exit is reversible during cellular quiescence, a process essential for stem cell maintenance and thereby for tissue regeneration. Quiescent tumour stem cells are present in early cancer metastasis, a phenomenon called “cancer dormancy”, which causes failure of common therapies targeting the cycling cells.

Progression through the cell cycle is orchestrated by a complex interplay of cell cycle regulators such as the cyclins, which are finely regulated at the level of gene expression, protein synthesis, degradation and phosphorylation. The cyclins activate the cyclin-dependent kinases, which promote cell cycle progression.

Specifically, the team investigates the molecular mechanisms of transcriptional regulation of the cyclin genes by the Muv-B complexes, during quiescence and mitosis initiation. The team is also focused on the anaphase-promoting complex (APC/C), which is the key regulator of chromosome segregation, mitosis exit and G1 phase.

To perform these studies the team combines biochemical reconstitution and analysis with integrative structural biology approaches, which include x-ray crystallography, cryo-electron microscopy, NMR and biomolecular mass spectrometry. The structural information is used to build structure-based hypotheses that will be tested in biochemical and biophysical assays, and in functional studies in cells. This information will elucidate the effects of documented cancer mutations affecting these complexes, and will give the basis for the design of novel anti-cancer drugs.

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