Our group is interested in the regulation of DNA recombination and chromosome segregation during the mitotic and the meiotic cell cycle. In particular, we have recently identified new genes involved in (1) the repair of double strand breaks (DSBs) and in (2) the generation of DSBs in meiosis. In addition, (3) we have generated mouse models with conditional knock out alleles for CDC20 or CDH1 (two activators of the Anaphase Promoting Complex or Cyclosome - APC/C) and are studying the role of these proteins in chromosome stability, cell cycle exit and cell differentiation.

Our main objectives are:

•     Identification of new genes involved in the cellular response to DNA damage. We have screened the complete set of approximately 5,000 viable S. cerevisiae haploid deletion mutants to identify genes that, when deleted, confer sensitivity or resistance to Trabectedin, a compound that induces DSBs. Many of the genes are already known but some of them are unknown or poorly understood. We plan to study these genes as potential candidates to participate in the cellular response to DNA damage.
•   Coordination between DNA replication, DSB formation, and chromosome segregation in meiosis. We have deleted 175 genes of unknown function that are upregulated during fission yeast meiosis. Among the new proteins identified we have focussed in the molecular machine (dynein-dynactin complex) responsible for the movement of the meiotic chromosomal bouquet during prophase, second, the function of Rec24, Rec25 and Rec27 in meiotic recombination and chromosome segregation and, finally, the role of the Septation Initiation Network (SIN) pathway in meiosis.
•     In vivo analysis of Cdc20 and Cdh1 (Fizzy-relate in chromosome segregation, cell cycle exit and cell differentiation.In collaboration with Dr Marcos Malumbres (CNIO) we have constructed knock out mice for the CDC20 or the CDH1 genes. These conditional knock out mouse models are based on the Cre-Lox system and will allow the functional analysis of these APC activators in vivo. Cdh1-deficient cells display a reduced proliferation rate due to premature and inefficient S phase and delayed exit from mitosis. Moreover, Cdh1-null cells accumulate numeric and structural chromosomal aberrations, revealing an important contribution of Cdh1 to the maintenance of genomic stability. Consistent with this observation, Cdh1 heterozygous animals display increased susceptibility to spontaneous tumours late in life.