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CELL CYCLE CONTROL PATHWAYS INVOLVED IN THE PROTECTION OF GENOMIC INTEGRITY, PROLIFERATION AND CANCER
The objective of our work is to identify novel cell cycle control elements and pathways involved in the protection of genomic integrity and the regulation of cell proliferation. Our recent work has focused on the S phase checkpoint, a surveillance mechanism that responds to DNA damage and replication fork blocks. In response to such genotoxic insults, the checkpoint attenuates chromosome replication to minimize the occurrence of genomic instability, and arrests cell cycle progression to provide time for repair. When the checkpoint response is impaired, cells may divide with incompletely replicated or damaged chromosomes, resulting in genomic instability, the driving force of malignant transformation and progression. The S phase checkpoint constitutes an anti-cancer barrier in early human tumorigenesis.
Despite the critical role that the S phase checkpoint plays, many aspects of its response remain elusive. To identify new checkpoint targets we have carried out different experimental approaches, including biochemical assays, genetic screens, and proteomic analyses. We have thus identified that the S phase cyclins, the activating subunits of the Cyclin Dependent Kinase (CDK) that triggers DNA replication, are regulated by the checkpoint. More recently, we have identified Dbf4, the activator subunit of the second essential S phase kinase DDK (Dbf4 Dependent Kinase), as one critical target through which the checkpoint blocks the activation of origins of replication, to slow the rate of DNA replication in response to genotoxic stress. Cancer cells are characteristically deficient in downregulating replication in response to DNA damage. We have generated a bypass mutant that fires origins despite the presence of DNA damage or replication stress, and therefore we count now on a powerful tool to examine the role that such control plays to prevent genomic instability.
In addition to continuing our work with the S phase checkpoint, we are currently investigating some unknown aspects on how eukaryotic cells subordinate progression into mitosis to the complete and correct conclusion of DNA replication.
P.I. background:
- PhD 1994 (UAB).
- Research Fellow 1996-1999 (Anindya Dutta's lab, Harvard Medical School).
- Research Fellow 2000-2002 (John Diffley's lab, Cancer Research UK, London Research Institute).
- Investigador Ramon y Cajal 2003-2008.
Former lab members went on to become:
- Anna Travesa, Research Associate at Curt Wittenberg's lab, Scripps Research Institute, San Diego, California.
- Nathalie Guibourt, Senior Scientist in Molecular Biology for Medical Translation Research, Celgene Institute of Translational Research Europe, Seville.
- Alba Duch, Postdoctoral Fellow at Francesc Posas' lab, Universitat Pompeu Fabra, Barcelona.
- Angel Guerra-Moreno, Postdoctoral Fellow at Jose Ayte's lab, PRBB, Barcelona.
