c/o IFOM-IEO Campus
Via Adamello, 16 - 20139 Milan, Italy
Tel: +39 02 574303238 - Fax: +39 02 574303231
The control of genome integrity is of pivotal importance for the cell. Failures in maintaining genome stability inevitably result in the accumulation of mutations, genome rearrangements, cell death and cancer. We study those cellular pathways that protect the stability of eukaryotic chromosomes.
CONTROL OF GENOME INTEGRITY DURING S PHASE
S-phase topology. Replicating chromosomes undergo topological transitions to coordinate replication fork progression with sister chromatid cohesion and chromosome condensation. We study the contribution of different DNA topoisomerases (Type I and Type II topoisomerases) in assisting fork progression in front of transcription units and at termination of DNA synthesis. We are also investigating the connections between chromatin remodeling factors and S-phase topological events.
Replication checkpoints. The ATM and ATR-mediated checkpoints coordinate replication with recombination and protect fork stability in response to replication stress induced by DNA damaging agents (often chemotherapeutic drugs) or by oncogenes. We study the physical events occurring at replication forks when replicating chromosomes are challenged by replication stress. These mechanisms have important implications for the human genome instability diseases Ataxia telangiectasia and Seckel syndromes.
THE CELLULAR RESPONSE TO DNA DAMAGE
Checkpoint activation. Activation of the ATM and ATR-dependent DNA damage response is influenced by the cell cycle stage and depends on the accumulation of specific checkpoint signals. We are investigating those pathways that influence DNA damage checkpoint activation (cyclin dependent kinase and chromatin remodeling activities) under conditions in which cells experience massive DNA damage or specific DNA lesions such as a single double strand break.
DNA helicases preventing genome instability. DNA helicases are enzymes that control the fundamental aspects of DNA metabolism, such as replication, recombination and transcription. We are investigating the functions of certain specialized DNA helicases (RecQ and Senataxin helicases) that are defective in a group of genome instability and neurodegenerative syndromes.
PHARMACOGENOMIC STUDIES ON ANTICANCER DRUGS
Chemical genetic profiles. A variety of anticancer drugs interfere with the DNA damage response and/or with the chromosome replication process. Using a yeast-based genetic system (yeast gene knock out libraries and allele specific mutant collections) we carry out chemical genetic profiles of anticancer drugs to identify those cellular pathways influencing cell sensitivity/resistance to the drug of interest. Mechanist studies are also employed.