Maekiniemi M, Hillukkala T, Tuusa J, Reini K, Vaara M, Huang D, Pospiech H, Majuri I, Westerling T, Maekelae TP, Syvaeoja JE

Biocenter Oulu and the Department of Biochemistry, University of Oulu, P. O. Box 3000, Oulu FIN-90014, Finland.

Topoisomerase IIbeta-binding protein (TopBP1), a human protein with eight BRCT domains, is similar to Saccharomyces cerevisiae Dpb11 and Schizosaccharomyces pombe Cut5 checkpoint proteins and closely related to Drosophila Mus101. We show that human TopBP1 is required for DNA replication and that it interacts with DNA polymerase epsilon. In S phase TopBP1 colocalizes with Brca1 to foci that do not represent sites of ongoing DNA replication. Inhibition of DNA synthesis leads to relocalization of TopBP1 together with Brca1 to replication forks, suggesting a role in rescue of stalled forks. DNA damage induces formation of distinct TopBP1 foci that colocalize with Brca1 in S phase, but not in G(1) phase. We also show that TopBP1 interacts with the checkpoint protein hRad9. Thus, these results implicate TopBP1 in replication and checkpoint functions.

Mesh Terms:
Animals, BRCA1 Protein, Carrier Proteins, Cell Cycle Proteins, Cell Nucleus, Chromosome Mapping, Cloning, Molecular, Cytoplasm, DNA Damage, DNA Polymerase II, DNA Repair, DNA Replication, DNA, Complementary, DNA-Binding Proteins, Drosophila, Drosophila Proteins, Ecdysone, Fungal Proteins, Hela Cells, Humans, In Situ Hybridization, Fluorescence, Mice, Nuclear Proteins, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, S Phase, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Signal Transduction, Time Factors, Transglutaminases, Tumor Cells, Cultured, Two-Hybrid System Techniques

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