Current and previous funding North West Cancer Research (CR947) Functions of mismatch repair proteins in the cellular response to nucleoside analogues. From 01.07.2013 North West Cancer Research Fund (CR675). Role of the XPG homologue Rad13 of fission yeast in nucleotide excision repair, base excision repair and transcription. 01.02.2005-31.05.2008 North West Cancer Research Fund (CR676). Function of the MutS homologue Msh3 in DNA damage tolerance. 01.01.2005-31.12.2007 Swiss National Science Foundation (31-58840.99). Involvement of damage-recognition proteins in repair of mismatched DNA. 01.04.2000-31.05.2003 Teaching Module organizer MSE-3013 (3rd year research projects) Lecturer in MSE-2025 (Molecular Biology and Biochemistry)

Dr Fleck is interested in genome stability, particularly nucleotide excision repair (NER), and mismatch repair (MMR), which uses the yeast Schizosaccharomyces pombe as model. His current research also focusses on the characterisation of Ddb1. In recent years it has been shown that Ddb1 is not only involved in NER, but is part of an E3 ubiquitin ligase complex that controls stability of proteins in a cell cycle specific manner and in response to DNA damage. One such target is Spd1, which is a negative regulator of ribonucleotide reductase (RNR). RNR catalyses the rate limiting step in dNTP synthesis. During replication and in response to DNA damage, Spd1 is poly-ubiquitinated by the E3 ligase complex and degraded by the proteasome. This activates RNR, thereby providing the cells with dNTP required for DNA synthesis. NER proteins are further characterised with respect to their functions in response to chemotherapeutic drugs and MMR-mediated stability of repetitive DNA sequences.

Vejrup-Hansen, R., Fleck, O., Landvad, K., Fahnøe, U., Broendum, S. S., Schreurs, A. S., Kragelund, B. B., Carr, A. M., Holmberg, C. and Nielsen, O. (2014) Spd2 assists Spd1 in the modulation of ribonucleotide reductase architecture but does not regulate deoxynucleotide pools. J. Cell Sci. 127: 2460-2470. Fleck, O., Vejrup-Hansen, R., Watson, A., Carr, A. M, Nielsen, O. and Holmberg, C. (2013) Spd1 accumulation causes genome instability independently of ribonucleotide reductase activity but functions to protect the genome when deoxynucleotide pools are elevated. J. Cell Sci. 126: 4985-4994. Vejrup-Hansen, R., Mizuno, K., Izumi Miyabe, I., Fleck, O., Murray, J. M., Carr, A. M. and Nielsen, O. (2011) Schizosaccharomyces pombe Mms1 channels repair of perturbed replication into Rhp51 independent homologous recombination. DNA Repair 10: 283-295. Moss, J., Tinline-Purvis, H., Walker, C. A., Folkes, L. K., Stratford, M. R., Hayles, J., Hoe, K. L., Kim, D. U., Park, H. O., Kearsey, S. E., Fleck, O., Holmberg, C., Olaf Nielsen, O. and Humphrey, T. C. (2010) Break-induced ATR and Ddb1-Cul4Cdt2 ubiquitin ligase-dependent nucleotide synthesis promotes homologous recombination repair in fission yeast. Genes & Dev. 24: 2705-2716. Nestoras, K., Mohammed, A. H., Schreurs, A. S., Fleck, O., Watson, A. T., Poitelea, M., O'Shea, C., Chahwan, C., Holmberg, C., Kragelund, B. B., Nielsen, O., Osborne, M., Carr, A. M. and Liu, C. (2010) Regulation of ribonucleotide reductase by Spd1 involves multiple mechanisms. Genes & Dev. 24:1145-1159. Tubbs, J. L., Latypov, V., Kanugula, S., Butt, A., Melikishvili, M., Kraehenbuehl, R., Fleck, O., Marriott, A., Watson, A. J., Verbeek, B., McGown, G., Thorncroft, M., Santibanez-Koref, M. F., Millington, C., Arvai, A. S., Kroeger, M. D., Peterson, L. A., Williams, D. M., Fried, M. G., Margison, G. P., Pegg, A. E. and Tainer, J. A. (2009) Flipping of alkylated DNA damage bridges base and nucleotide excision repair. Nature 459: 808-313.