My research group works on the regulation and mechanism of eukaryotic DNA replication, a process intrinsic to cell reproduction in all organisms. DNA replication is tightly regulated, only occurring in cells which are committed to divide. Replication starts from thousands of origins in the genome and several controls prevent origins from firing more than once per cell cycle, thus ensuring that only two copies of each chromosome are produced. The amazing fidelity of the copying process (one error per 109 nucleotides) is ensured in part by checkpoint mechanisms that delay replication if DNA is damaged and repair mechanisms which fix replication errors. Genome instability can result from defects in DNA replication and this is a factor in cancer development.

Guarino, E., I. Salguero, and S.E. Kearsey. (2014) Cellular regulation of ribonucleotide reductase in eukaryotes. Seminars in cell & developmental biology. 30:97-103. Palles, et al. (2013) Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nature genetics. 45:136-144. Hua, H., M. Namdar, O. Ganier, J. Gregan, M. Mechali, and S.E. Kearsey. (2013) Sequential steps in DNA replication are inhibited to ensure reduction of ploidy in meiosis. Molecular biology of the cell. 24:578-587. Havens et al. (2012) Direct role for proliferating cell nuclear antigen in substrate recognition by the E3 ubiquitin ligase CRL4Cdt2. The Journal of biological chemistry. 287:11410-11421. Salguero, I., E. Guarino, M.E. Shepherd, T.D. Deegan, C.G. Havens, S.A. MacNeill, J.C. Walter, and S.E. Kearsey. (2012) Ribonucleotide reductase activity is coupled to DNA synthesis via proliferating cell nuclear antigen. Current biology : CB. 22:720-726. Tvegard, T., Soltani, H., Skjolberg, H.C., Krohn, M., Nilssen, E.A., Kearsey, S.E., Grallert, B. and Boye, E. (2007) A novel checkpoint mechanism regulating the G1/S transition. Genes Dev, 21, 649-654.