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Cell programming pathways
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The initiation of DNA replication represents a committing step in cell proliferation, and depends upon the non-overlapping activity of two enzymes, S-phase CDK2 (S-CDK2) and Dbf4-dependent CDC7 (DDK) kinase. Crosstalk between DNA replication initiation and cell cycle progression is an essential component of the programme to maintain genome integrity, which is comprised of multiple checkpoints. G1-S transition checkpoints govern the decision to allow or to prohibit DNA synthesis, depending on the level of metabolic reserves, bioenergetics and the integrity of DNA. Defects in G1-S checkpoints commonly occur during malignant transformations.
My research aims to answer the following fundamental questions: (1) How do human cells couple the cell cycle machinery to cellular metabolism essential for G1-S progression? (2) What is the crosstalk between metabolic and energetic requirements that are integrated with mitochondria and the initiation of DNA replication? (3) How do cells monitor and control the start of DNA replication under replicative genotoxic stress? (4) What is the role of p53 and DNA replication initiation in stem cell homeostasis?
The link between the metabolic checkpoint, mitochondria and DNA replication initiation. My recent work has contributed to elucidation of the metabolic nature of the restriction point in G1-S, in which APC/C-Cdh1 plays a fundamental role by linking the all-important provision of glucose and glutamine to messages required for cell duplication (Proc Natl Acad Sci. 2011a and Proc Natl Acad Sci. 2011b). Expression of PFKFB3, an enzyme essential for the enhancement of glycolysis, is detectable concomitantly with other proteins responsible for G1 to S phase progression. PFKFB3 protein and a peak in the rate of lactate production are present only transiently at G1-S, following a decrease in the activity of the ubiquitin ligase APC/C-Cdh1, which targets PFKFB3 for degradation. The subsequent upregulation of glycolysis by PFKFB3 provides the glucose necessary for the synthesis of macromolecules. My current research explores the role of transient glycolysis in the proliferative cell cycle, and how cellular bioenergetics and mitochondrial dynamics are translated to cyclin E accumulation, cyclin E/CDK2 activity and DNA replication initiation.
Perturbance of DNA replication initiation induces origin of replication activation checkpoint. I have also discovered the origin of activation checkpoint that is critically dependent on three axes coordinated through the Forkhead transcription factor FoxO3a (EMBO J 2010). SILAC-based high resolution MS proteomics showed that the arrested phenotype of normal fibroblasts involves active rather than passive cellular and metabolic adaptation, and that the Cdc7-depleted proteome maintains cellular arrest by initiating a dynamic quiescence-like and catabolic response that promotes cellular survival (J Proteome Res. 2010 and J Proteome Res. 2013). The reliance on several tumour suppressor proteins commonly inactivated in human tumours provides a strong mechanistic basis for the differential killing of tumour versus normal cells if Cdc7 function is lost. The therapeutic targeting of the DNA replication initiation machinery thus constitutes one of the focuses of my research.
The physiological regulation of origin of replication activation checkpoint. Replicative genotoxic stress stimulates a molecular response to suppress CDK2 activity, which relies on p53-induced transcription of p21WAF1. However, the p53 stress pathway has evolved multiple strategies which combine transcriptional, post-transcriptional and post-translational mechanisms. My present work also investigates how replicative genotoxic stress targets and regulates the DNA replication initiation CDC7 kinase, and how this is linked to known tumour suppressor pathways.
- 2013-date Honorary Research Fellow (Ernst Jung Scholarship), WIBR, UCL
- 2006-2013 Postdoctoral Research Fellow,Department of Pathology, UCL
- 1999-2003 PhD Medical University of Vienna, Austria
- 2000-2003 MSc in Tumour Biology, Medical University of Vienna, Austria
- 2000-2003 MSc in Natural Sciences, Medical University of Vienna, Austria
- 1987-1991 B.Sc.in Pharmacy, University “St. Kiril and Methodius” Macedonia
20013-present Ernst Jung Scholarship
Mulvey C, Tudzarova S, Crawford M, Williams G, Stoeber K and Godovac-Zimmermann J (2013). Subcellular proteomics reveals a role for nucleo-cytoplasmic shuttling at the DNA Replication Origin Activation Checkpoint. J Proteome Res. 12:1436-53
Tudzarova S, Colombo SL, Stoeber K, Carcamo S, Williams GH, Moncada S. (2011) Two ubiquitin ligases, APC/C-Cdh1 and SKP1-CUL1-F (SCF)-beta-TrCP, sequentially regulate glycolysis during the cell cycle. Proc Natl Acad Sci. 108:5278-83
Colombo SL, Palacios-Callender M, Frakich N, Carcamo S, Kovacs I, Tudzarova S, Moncada S. (2011) Molecular basis for the differential use of glucose and glutamine in cell proliferation as revealed by synchronized HeLa cells. Proc Natl Acad Sci. 108:21069-74
Gooding M, Tudzarova S, Worthington RJ, Kingsbury SR, Rebstock AS, Dube H, Simone MI, Visintin C, Lagos D, Quesada JM, Laman H, Boshoff C, Williams GH, Stoeber K, Selwood DL. (2011) Exploring the interaction between siRNA and the SMoC biomolecule transporters: implications for small molecule-mediated delivery of siRNA. Chem Biol Drug Des. 79:9-21
Tudzarova S, Trotter MW, Wollenschlaeger A, Mulvey C, Godovac-Zimmermann J, Williams GH, Stoeber K. (2010) Molecular architecture of the DNA replication origin activation checkpoint. EMBO J. 29:3381-94
Mulvey C, Tudzarova S, Crawford M, Williams G, Stoeber K, Godovac-Zimmermann J. (2010) Quantitative proteomics reveals a "poised quiescence" cellular state after triggering the DNA replication origin activation checkpoint. J Proteome Res. 9:5445-60
Kulkarni AA, Kingsbury SR, Tudzarova S, Hong HK, Loddo M, Rashid M, Rodriguez-Acebes S, Prevost AT, Ledermann JA, Stoeber K, Williams GH. (2009) Cdc7 kinase is a predictor of survival and a novel therapeutic target in epithelial ovarian carcinoma. Clin Cancer Res. 15:2417-25
Further publication information can be viewed at http://iris.ucl.ac.uk/iris/browse/profile?upi=STUDZ42