The research of our group focuses on the molecular mechanism of the DNA damage response in human cells and its link to cancer and other processes like apoptosis or meiosis.
In the last years we were mainly interested in studying the ATR-Chk1 pathway and particularly the regulation of Claspin, a critical intermediate between ATR and Chk1. We discovered that Claspin is degraded by proteasome during the recovery from a checkpoint during the transition between G2 and mitosis. This process was dependent on beta-TrCP ubiquitination (Mamely et al, 2006). Moreover, we described a role of Claspin during apoptosis, as it is degraded by proteasome during apoptosis, and its lack contributes to the apoptotic response (Semple et al, 2007).
Our laboratory is presently interested in two main areas:
- To study how ubiquitin modifications can regulate different DNA damage response pathways, including Claspin ubiquitination. Recently, we have isolated a new de-ubiquitin enzyme that regulates Claspin levels during G1 and we are in the process of characterizing this process into more detail (Martín and Freire, unpublished data).
- To investigate the link between the cell cycle regulator Wee1 and the DNA damage response. We recently discovered that cells lacking Wee1 display a DNA damage response during S phase. Interestingly, this process depends on the Mus81-Eme1 endonuclease that becomes activated in those conditions (Dominguez-Kelly et al, 2011). We are currently investigating the molecular details of regulation of Mus81 by Wee1.
Mamely I, van Vugt MA, Smits VA, Semple JI, Lemmens B, Perrakis A, Medema RH, Freire R (2006). Polo-like kinase-1 controls proteasome-dependent degradation of Claspin during checkpoint recovery. Curr Biol 16: 1950-1955.
Semple JI, Smits VA, Fernaud JR, Mamely I, Freire R (2007). Cleavage and degradation of Claspin during apoptosis by caspases and the proteasome. Cell Death Differ. 14: 1433-1442.
Domínguez-Kelly R, Martín Y, Koundrioukoff S, Tanenbaum ME, Smits VAJ, Medema RH, Debatisse M, and Freire R (2011). Wee1 controls genomic stability during replication by regulating the Mus81-Eme1 endonuclease. J Cell Biol. 194: 567-579.