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Prof Corrado Santocanale Ph.D
|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&D site in Nerviano, Italy (former Pharmacia/Pfizer 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 has recently returned to academia to pursue his studies. 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 is entering 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.|
Research in my lab is centered on studying the mechanisms of DNA replication in cancer cells and exploiting the results of this research for therapeutic purposes. Active projects focus on understanding the cellular functions and regulation of Cdc7 kinase (A) and on characterizing inhibitors of Cdc7 kinase activity in Multiple Myeloma and Chronic Lymphocytic Leukaemia (B). Recently we have developed a technique that will allow us to study how chromatin assembly is coupled with the duplication of DNA (C).
A) 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. Human Cdc7 has two cyclin-like binding partners which form either a Cdc7/Dbf4 complex or a Cdc7/Drf1 complex-their reciprocal roles are not yet defined. Biochemical, structural and functional approaches are employed to characterize the role of human Cdc7. Specific goals are:
Define reciprocal roles of the Dbf4 and Drf1 regulatory subunits
Identify new roles/substrates of the kinase
Determine the structure of kinase active site and other structural domains
Determine the impact of miRNA on Cdc7 activity
Key to these projects is the access to a MS/proteomic facility. A great effort was put into the development of in house infrastructure that can currently support both protein ID and phosphosite ID. This resource and protocols are made available to NUIG researchers.
B) Cdc7 inhibitors have shown antitumor activity in broad spectrum of preclinical cancer models including solid and leukemia xenografts, carcinogen induced and transgenic models. Phase I clinical studies are ongoing. A key question for this new class of drugs is to identify those cancer types in which they may be more efficacious. Together with Micheal O'Dwyer (Prof. of Hematology and Hospital consultant) we have been testing the activity and mechanism of action of Cdc7 inhibitors in cells from MM and CLL patents. Cellular co-culture systems that mimic the protective microenvironment niche of the lymph nodes have been developed for this purpose.
C) Replication of DNA and duplication of the epigenetic information are critical to the transmission of the genetic material from the parental cell to the two daughter cells and for specifying cell-type identity of the two daughter cells. To investigate how these processes are regulated and coordinated, it is important to determine the identity of the proteins that are either stably or transiently associated with newly synthesized DNA. We have devised an experimental procedure that allows newly synthesized chromatin to be efficiently captured and analyzed. We have termed this DNA mediated chromatin pull-down (Dm-ChP). Dm-ChP is a highly specific and flexible technique. Current work is focused on identifying the protein component of newly synthesized chromatin and in assessing qualitative and quantitative changes in this protein fraction caused by the normal temporal program of DNA replication as well as by perturbation of the DNA replication machinery.
Cell Cycle, DNA replication, Cancer terapeutics
|Diffley JF, Bousset K, Labib K, Noton EA, Santocanale C and Tercero JA. (2000) 'Coping with and recovering from hydroxyurea-induced replication fork arrest in budding yeast' In: Cold Spring Harbor symposia on quantitative biology. USA: Cold Spring Harbor press. [Details]|
Peer Reviewed Journals
|Rainey MD, Harhen B, Wang GN, Murphy PV, Santocanale C (2013) 'Cdc7-dependent and -independent phosphorylation of Claspin in the induction of the DNA replication checkpoint'. Cell Cycle, 12 (10). [Details]|
|Stone, JG,Siedlak, SL,Tabaton, M,Hirano, A,Castellani, RJ,Santocanale, C,Perry, G,Smith, MA,Zhu, XW,Lee, HG (2011) 'The Cell Cycle Regulator Phosphorylated Retinoblastoma Protein Is Associated With Tau Pathology in Several Tauopathies'. Journal Of Neuropathology And Experimental Neurology, 70 :578-587. [DOI] [Details]|
|Martin, L., Rainey, M., Santocanale, C., Gardner, L.B. (2011) 'Hypoxic activation of ATR and the suppression of the initiation of DNA replication through cdc6 degradation'. Oncogene, . [Details]|
|Napolitano, C,Natoni, A,Santocanale, C,Evensen, L,Lorens, JB,Murphy, PV (2011) 'Isosteric replacement of the Z-enone with haloethyl ketone and E-enone in a resorcylic acid lactone series and biological evaluation'. Bioorganic & Medicinal Chemistry Letters, 21 :1167-1170. [DOI] [Details]|
|Natoni, A,Murillo, LS,Kliszczak, AE,Catherwood, MA,Montagnoli, A,Samali, A,O'Dwyer, M,Santocanale, C (2011) 'Mechanisms of Action of a Dual Cdc7/Cdk9 Kinase Inhibitor against Quiescent and Proliferating CLL Cells'. Molecular Cancer Therapeutics, 10 :1624-1634. [DOI] [ARAN Link] [Details]|
|Kliszczak, AE,Rainey, MD,Harhen, B,Boisvert, FM,Santocanale, C (2011) 'DNA mediated chromatin pull-down for the study of chromatin replication'. Scientific Reports, 1 . [DOI] [ARAN Link] [Details]|
|Menichincheri M, Albanese C, Alli C, Ballinari D, Bargiotti A, Caldarelli M, Ciavolella A, Cirla A, Colombo M, Colotta F, Croci V, D'Alessio R, D'Anello M, Ermoli A, Fiorentini F, Forte B, Galvani A, Giordano P, Isacchi A, Martina K, Molinari A, Moll JK, Montagnoli A, Orsini P, Orzi F, Pesenti E, Pillan A, Roletto F, Scolaro A, TatÃ² M, Tibolla M, Valsasina B, Varasi M, Vianello P, Volpi D, Santocanale C, Vanotti E (2010) 'Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding'. Journal Of Medicinal Chemistry, 53 (20):7296-7315. [DOI] [Details]|
|Swords R, Mahalingam D, O'Dwyer M, Santocanale C, Kelly K, Carew J, Giles F (2010) 'Cdc7 kinase - a new target for drug development'. European Journal Of Cancer, 46 (1):33-40. [DOI] [Details]|
|Vanotti E, Amici R, Bargiotti A, Berthelsen J, Bosotti R, Ciavolella A, Cirla A, Cristiani C, D'Alessio R, Forte B, Isacchi A, Martina K, Menichincheri M, Molinari A, Montagnoli A, Orsini P, Pillan A, Roletto F, Scolaro A, Tibolla M, Valsasina B, Varasi M, Volpi D, Santocanale C (2008) 'Cdc7 kinase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships'. Journal Of Medicinal Chemistry, 51 (3):487-501. [DOI] [Details]|
|Tenca P, Brotherton D, Montagnoli A, Rainoldi S, Albanese C, Santocanale C (2007) 'Cdc7 is an active kinase in human cancer cells undergoing replication stress'. Journal Of Biological Chemistry, 282 (1):208-215. [DOI] [Details]|
|Montagnoli A, Valsasina B, Brotherton D, Troiani S, Rainoldi S, Tenca P, Molinari A, Santocanale C (2006) 'Identification of Mcm2 phosphorylation sites by S-phase-regulating kinases'. Journal Of Biological Chemistry, 281 (15):10281-10290. [DOI] [Details]|
|Montagnoli A, Tenca P, Sola F, Carpani D, Brotherton D, Albanese C, Santocanale C (2004) 'Cdc7 inhibition reveals a p53-dependent replication checkpoint that is defective in cancer cells'. Cancer Research, 64 (19):7110-7116. [DOI] [Details]|
|Montagnoli A, Bosotti R, Villa F, Rialland M, Brotherton D, Mercurio C, Berthelsen J, Santocanale C (2002) 'Drf1, a novel regulatory subunit for human Cdc7 kinase'. Embo Journal, 21 (12):3171-3181. [DOI] [Details]|
|Diffley JF, Bousset K, Labib K, Noton EA, Santocanale C, Tercero JA (2000) 'Coping with and recovering from hydroxyurea-induced replication fork arrest in budding yeast'. Cold Spring Harb Symp Quant Biol, 65 :333-342. [Details]|
|Santocanale C, Diffley JF (1998) 'A Mec1- and Rad53-dependent checkpoint controls late-firing origins of DNA replication'. Nature, 395 (6702):615-618. [DOI] [Details]|
|Cocker JH, Piatti S, Santocanale C, Nasmyth K and Diffley JF. (1996) 'An essential role for the Cdc6 protein in forming the pre-replicative complexes of budding yeast'. Nature, 379 :180-182. [Details]|
|Shimizu K, Santocanale C, Ropp PA, Longhese MP, Plevani P, Lucchini G, Sugino A (1993) 'Purification and characterization of a new DNA polymerase from budding yeast Saccharomyces cerevisiae. A probable homolog of mammalian DNA polymerase beta'. Journal Of Biological Chemistry, 268 (36):27148-27153. [Details]|
|Santocanale C, Locati F, Muzi Falconi M, Piseri A, Tseng B, Lucchini G and Plevani P. (1992) 'Overproduction and functional analysis of DNA primase subunits from yeast and mouse'. Gene, 113 :199-205. [Details]|
|Francesconi S, Longhese MP, Piseri A, Santocanale C, Lucchini G, Plevani P (1991) 'Mutations in conserved yeast DNA primase domains impair DNA replication in vivo'. Proc Natl Acad Sci U S A, 88 (9):3877-3881. [Details]|
|Murillo, L; Natoni, A; O’Connell, E; Fitzgerald, J; O’Dwyer, M; Santocanale, C (2013) Development of a High-Throughput Screening assay for the identification of compounds affecting Cdc7 dependent MCM helicase phosphorylation Irish Association for Cancer Research [Details]|
|Krawczyk, J,Egan, C,Mulvihill, M,Webber, M,Murillo, L,Ingoldsby, H,Santocanale, C,Callagy, G,O'Dwyer, MC (2009) Increased Activity of the S Phase Kinase Cdc7 Is Associated with Poor Outcome in Diffuse Large B Cell Lymphoma (DLBCL) , pp.760-760 [Details]|
|Natoni, A,Hayat, A,Montagnoli, A,Callagy, G,Samali, A,Santocanale, C,O'Dwyer, MC (2009) BLOOD PHA767491, a Dual Cdc7/CDK9 Inhibitor, with Potential to Target Both Proliferation and Survival in CLL , pp.934-934 [Details]|
|Coyne, MRE; Naughton, S; Hayden, PJ; Montagnoli, A; O'Dwyer, ME; Santocanale, C (2009) Targeting Cdc7 Kinase in Multiple Myeloma . In: Source: BLOOD eds. ASH annual meeting 2009 , pp.22 1479-1480 [Details]|
|Montagnoli, A,Vanotti, E,Rainoldi, S,Marchesi, V,Ciavolella, A,Croci, V,Patton, V,Albanese, C,Santocanale, C,Moll, J (2008) EJC SUPPLEMENTS Discovery and characterization of a new potent orally available CdC7 inhibitor with anti-tumor activity , pp.116-116 [Details]|
|Bargiotti, A,Berthelsen, J,Bossi, R,Ciavolella, A,Cirla, A,Cristiani, C,Croci, V,D'Alessio, R,Forte, B,Martina, K,Molinari, A,Montagnoli, A,Orsini, P,Orzi, F,Pezzetta, D,Pillan, A,Poggesi, I,Roletto, F,Santocanale, C,Scolaro, A,Tibolla, M,Valsasina, B,Volpi, D,Vanotti, E (2007) MOLECULAR CANCER THERAPEUTICS Cdc7 kinase inhibitors: 7-Substituted pyrrolopyridinones as potent and orally active antitumor agents , pp.3409-3409 [Details]|
|Swords, R,Mahalingam, D,O'Dwyer, M,Santocanale, C,Kelly, K,Carew, J,Giles, F (2010) Cdc7 kinase - A new target for drug development. Reviews [DOI] [Details]|
|Coyne, MRE,Naughton, S,Hayden, PJ,Montagnoli, A,O'Dwyer, ME,Santocanale, C (2009) Targeting Cdc7 Kinase in Multiple Myeloma. Meeting [Details]|
|Involved in the education of second year Biochemistry and Medicine undergraduate students. Also contributing to several post-graduate courses.|
| Anna Kliszczak - PhD
Raffaella D'Auria - Research Master
Current Postgraduate Students
|Mark Coyne, Doctorate - Ph.D. - Supervisor|
|Kevin Wu, Doctorate - Structured PhD (Science) - Supervisor|
| Prof Michael O'Dwyer.
Dr Heinz Peter Nasheuer.
Dr Stefan Knap, Structural Genomic Consortium, University of Oxford, UK.
Dr Achille Peliccioli, Dipartimento di Scienze Biomolecolari e Biotecnologie University of Milan, Italy.
Dr Andrea Musacchio, Max-Planck Institute of Molecular Physiology, Dortmund, Germany.