Professor Corrado Santocanale received his Ph.D. in Cellular and Molecular Biology at the University of Milan, Italy, in 1993. His early work focused on the characterization of enzymes required for the duplication of the DNA in the yeast S. cerevisiae. He was then awarded an EU Marie Curie postdoctoral fellowship to work on the molecular mechanisms that control initiation of DNA replication at the Clare Hall Laboratories, Cancer Research UK, London. He spent eight years in the pharmaceutical industry at the Oncology R amp;D site in Nerviano, Italy (former PharmaciaPfizer and now Nerviano Medical Sciences) both as a group and as a project leader developing protein kinase inhibitors for the treatment of human cancers. He returned to academia in 2007. The major achievement in Cancer Drug Discovery was to propose and lead a program through all the stages of the pre-clinical drug discovery process delivering a compound with a novel mechanism of action that entered clinical trials. The major achievements in basic cancer research include: - Identification and characterization of the origin firing checkpoint, a biochemical pathway that is activated in response to the inhibition of DNA replication elongation thus preventing the activation of new replication origins. - Identification of the second cyclin like regulatory subunit of the human Cdc7 kinase. - The identification of a biochemical pathway, altered in cancer cells, responding to the inhibition of the Cdc7 kinase. Identification of the gene encoding the first eukaryotic DNA primase large subunit.

The process of DNA replication is the biggest threat for genome stability in all proliferating cells. Cancer cells in particular are subjected to replication stress after activation of proto-oncogenes into their oncogenic forms or due to deficiency in specific factors required for genome duplication. Thus aberrant DNA replication contributes to initiating and maintaining the cancerous state, while drugs targeting DNA synthesis have potent antitumor activity and are key component of current and novel chemotherapeutic regimens. Our laboratory is studying the mechanisms that regulate genome replication in human cells with particular emphasis on the Cell Division Cycle 7 kinase (CDC7). CDC7 acts as a molecular switch for DNA synthesis and is also thought to participate in several other processes that regulate normal cell cycle progression and chromosome dynamics.We have adopted chemical biology and gene editing approaches to characterize the molecular processes in which CDC7 is involved and to detect new substrates of the kinase. We are performing genome-wide CRISPRCas9 screens to identify genes that alter the cellular responses and make cells more sensitive or resistant to CDC7 inhibition.This information will be pivotal in understanding in what disease context emerging CDC7 inhibitors may be used for the cancer treatment, and in developing novel biomarkers, thus providing valuable information and tools for rationally driving patient selection and devising combination therapies in preclinical and clinical settings. We are also interested in understanding the roles of the Ubiquitin Specific Protease 9X (USP9X) which in context dependent manner can act as either an oncogene or a tumour suppressor. We have recently discovered that USP9X contributes to genome stability by promoting forks stability and efficient DNA repair, but by different mechanisms.In the past we have established a technique for the purification and characterization of proteins associated to newly replicated DNA that we called DNA mediated chromatin pull down (Dm-ChP). This technique has been particularly useful in understanding which proteins acts at forks during unperturbed replication, upon replication stress and in different genetic backgrounds. Cell Cycle, DNA replication, Cancer therapeutics

Biomolecules, DNA replication, Cell cycle, DNA repair, Cancer biology, Drug discovery and development