The main interest of our group is to understand how cells coordinate cell growth and division with cell differentiation. To study this biological problem we use two model organisms, the fission yeast Schizosaccharomyces pombe, a unicellular organism widely used in cell cycle research, and the mouse, where we analyse the physio-pathological consequences of knocking down cell cycle regulator genes in animal cells.

In fission yeast, we have recently described that the Greatwall-Endosulfine (Ppk18-Igo1, in fission yeast) pathway couples the nutritional environment to the cell cycle machinery by regulating PP2A/B55 activity. In the presence of nutrients, Greatwall (Ppk18) protein kinase is inhibited by TORC1 and PP2A/B55 is active. High levels of PP2A/B55 prevent the activation of mitotic Cdk1/Cyclin B and cells increase in size in G2 before undergoing mitosis. When nutrients are limiting, TORC1 activity declines and activation of Greatwall (Ppk18) leads to phosphorylation of Endosulfine (Igo1) and inhibition of PP2A/B55, which in turn allows full activation of Cdk1/Cyclin B and entry into mitosis with a smaller cell size.

The Greatwall-Endosulfine-PP2A/B55 pathway regulates cell size by coupling cell growth (TORC1 activity) to the cell cycle machinery (Cdk1/CyclinB)

In mice we are studying the function of the Anaphase Promoting Complex or Cyclosome (APC/C) and its cofactor Cdh1, an E3 ubiquitin ligase that targets many substrates for proteosomal degradation during G1. Our results indicate that Cdh1-deficient cells accumulate DNA breaks and show slow replication fork progression and increased origin activation, consistent with replication stress. We are currently investigating the role of APC/C-Cdh1 in preventing replicative stress and premature ageing.

APC/C-Cdh1 prevents premature entry into S-phase, genomic instability and tumour development