Prof Corrado Santocanale

Ph.D

Contact Details


Centre for Chromosome Biology (CCB)

Professor
SCHOOL OF NATURAL SCIENCES
NUI GALWAY

T: Ext. 4115
E: corrado.santocanale@nuigalway.ie
 
researcher

Biography

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 Interests

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
 

Peer Reviewed Journals

  Year Publication
(2016) 'Requirement for PLK1 kinase activity in the maintenance of a robust spindle assembly checkpoint'
O'Connor A, Maffini S;Rainey MD;Kaczmarczyk A;Gaboriau D;Musacchio A;Santocanale C (2016) 'Requirement for PLK1 kinase activity in the maintenance of a robust spindle assembly checkpoint'. Biology Open, 5 (1):11-19 [DOI] [ARAN Link] [Details]
(2015) 'Synthesis of Migrastatin Analogues as Inhibitors of Tumour Cell Migration: Exploring Structural Change in and on the Macrocyclic Ring'
Lo Re D, Zhou Y;Mucha J;Jones LF;Leahy L;Santocanale C;Krol M;Murphy PV (2015) 'Synthesis of Migrastatin Analogues as Inhibitors of Tumour Cell Migration: Exploring Structural Change in and on the Macrocyclic Ring'. Chemistry (Weinheim an der Bergstrasse, Germany), [DOI] [ARAN Link] [Details]
(2015) 'Molecular targets for novel drug development in pancreatic cancer'
Eimear O’ Reilly, Corrado Santocanale, Eva Szegezdi (2015) 'Molecular targets for novel drug development in pancreatic cancer'. Annals on Cancer Research, 2 (3) [Details]
(2014) 'A High Through-Put Screen for Small Molecules Modulating MCM2 Phosphorylation Identifies Ryuvidine as an Inducer of the DNA Damage Response'
FitzGerald, J,Murillo, LS,O'Brien, G,O'Connell, E,O'Connor, A,Wu, K,Wang, GN,Rainey, MD,Natoni, A,Healy, S,O'Dwyer, M,Santocanale, C (2014) 'A High Through-Put Screen for Small Molecules Modulating MCM2 Phosphorylation Identifies Ryuvidine as an Inducer of the DNA Damage Response'. Plos One, 9 [DOI] [Details]
(2013) 'Cdc7-dependent and -independent phosphorylation of Claspin in the induction of the DNA replication checkpoint'
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 :1560-1568 [DOI] [Details]
(2013) 'MicroRNA-29a regulates the benzo[a]pyrene dihydrodiol epoxide-induced DNA damage response through Cdc7 kinase in lung cancer cells'
Barkley, LR,Santocanale, C (2013) 'MicroRNA-29a regulates the benzo[a]pyrene dihydrodiol epoxide-induced DNA damage response through Cdc7 kinase in lung cancer cells'. Oncogenesis, 2 [DOI] [Details]
(2013) 'Characterization of a Dual CDC7/CDK9 Inhibitor in Multiple Myeloma Cellular Models'
Natoni A, Coyne MR, Jacobsen A, Rainey MD, O'Brien G, Healy S, Montagnoli A, Moll J, O'Dwyer M, Santocanale C (2013) 'Characterization of a Dual CDC7/CDK9 Inhibitor in Multiple Myeloma Cellular Models'. Cancers, 5 (3):901-918 [DOI] [Details]
(2013) 'Cell cycle-dependent formation of Cdc45-Claspin complexes in human cells is compromized by UV-mediated DNA damage'
Broderick, R,Rainey, MD,Santocanale, C,Nasheuer, HP (2013) 'Cell cycle-dependent formation of Cdc45-Claspin complexes in human cells is compromized by UV-mediated DNA damage'. Febs Journal, 280 :4888-4902 [DOI] [Details]
(2012) 'Hypoxic activation of ATR and the suppression of the initiation of DNA replication through cdc6 degradation'
Martin, L., Rainey, M., Santocanale, C., Gardner, L.B. (2012) 'Hypoxic activation of ATR and the suppression of the initiation of DNA replication through cdc6 degradation'. Oncogene, [Details]
(2011) 'The Cell Cycle Regulator Phosphorylated Retinoblastoma Protein Is Associated With Tau Pathology in Several Tauopathies'
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]
(2011) 'Isosteric replacement of the Z-enone with haloethyl ketone and E-enone in a resorcylic acid lactone series and biological evaluation'
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]
(2011) 'DNA mediated chromatin pull-down for the study of chromatin replication'
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]
(2011) 'Mechanisms of Action of a Dual Cdc7/Cdk9 Kinase Inhibitor against Quiescent and Proliferating CLL Cells'
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]
(2010) 'Cdc7 kinase - a new target for drug development'
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]
(2010) 'Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding'
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, Tatò 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]
(2008) 'Cdc7 kinase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships'
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]
(2007) 'Cdc7 is an active kinase in human cancer cells undergoing replication stress'
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]
(2006) 'Identification of Mcm2 phosphorylation sites by S-phase-regulating kinases'
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]
(2004) 'Cdc7 inhibition reveals a p53-dependent replication checkpoint that is defective in cancer cells'
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]
(2002) 'Drf1, a novel regulatory subunit for human Cdc7 kinase'
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]
(2000) 'Coping with and recovering from hydroxyurea-induced replication fork arrest in budding yeast'
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]
(1998) 'A Mec1- and Rad53-dependent checkpoint controls late-firing origins of DNA replication'
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]
(1996) 'An essential role for the Cdc6 protein in forming the pre-replicative complexes of budding yeast'
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]
(1993) 'Purification and characterization of a new DNA polymerase from budding yeast Saccharomyces cerevisiae. A probable homolog of mammalian DNA polymerase beta'
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]
(1992) 'Overproduction and functional analysis of DNA primase subunits from yeast and mouse'
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]
(1991) 'Mutations in conserved yeast DNA primase domains impair DNA replication in vivo'
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]

Book Chapters

  Year Publication
(2013) 'A cell culture system that mimics chronic lymphocytic leukemia cells microenvironment for drug screening and characterization'
Natoni A, O'Dwyer M, Santocanale C (2013) 'A cell culture system that mimics chronic lymphocytic leukemia cells microenvironment for drug screening and characterization' In: [DOI] [Details]
(2000) 'Coping with and recovering from hydroxyurea-induced replication fork arrest in budding yeast'
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]

Conference Publications

  Year Publication
(2014) Irish Association for Cancer Research
Fitzgerald, J; Murillo, L; O’Brien, G; O’Connell, E; O’Connor, A; Wu, K; Wang, GN; Rainey, MD; Natoni, A; Healy, S; O’Dwyer, M; Santocanale, C (2014) A high through put screen identifies Ryuvidine as a modulator of Cdc7 dependent phosphorylation of MCM2 and an inducer of the DNA damage response Irish Association for Cancer Research [Details]
(2013) Irish Association for Cancer Research
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]
(2009) Increased Activity of the S Phase Kinase Cdc7 Is Associated with Poor Outcome in Diffuse Large B Cell Lymphoma (DLBCL)
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]
(2009) PHA767491, a Dual Cdc7/CDK9 Inhibitor, with Potential to Target Both Proliferation and Survival in CLL
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]
(2009) ASH annual meeting 2009
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]
(2008) Discovery and characterization of a new potent orally available CdC7 inhibitor with anti-tumor activity
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]
(2007) Cdc7 kinase inhibitors: 7-Substituted pyrrolopyridinones as potent and orally active antitumor agents
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]

Abstract

  Year Publication
(2010) Dual Cdc7/Cdk9 kinase inhibitor, PHA-767491, targets both quiescent and proliferating CLL cells.
Santocanale, A,Natoni, A,Murillo, L,Catherwood, M,Montagnoli, A,Samali, A,O'Dwyer, M (2010) Dual Cdc7/Cdk9 kinase inhibitor, PHA-767491, targets both quiescent and proliferating CLL cells. Abstract [Details]

Meeting

  Year Publication
(2009) Targeting Cdc7 Kinase in Multiple Myeloma.
Coyne, MRE,Naughton, S,Hayden, PJ,Montagnoli, A,O'Dwyer, ME,Santocanale, C (2009) Targeting Cdc7 Kinase in Multiple Myeloma. Meeting [Details]

Reviews

  Year Publication
(2010) Cdc7 kinase - A new target for drug development.
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]

Teaching Interests

Involved in the education of second year Biochemistry and Medicine undergraduate students. Also contributing to several post-graduate courses. 

Internal Collaborators

  Name Description of Collaboration
Internal Collaborators
Prof Michael O'Dwyer.Dr Heinz Peter Nasheuer.

External Collaborators

  Name Organisation / Institute Country Description of Collaboration
External Collaborators
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.