BRCT domain-containing protein TopBP1 functions in DNA replication and damage response

Topoisomerase II beta -binding protein (TopBP1), a human protein with eight BRCT domains, is similar to Saccharomyces cerevisiae Dpb11 and Schizosacch aromyces pombe Cut5 checkpoint proteins and closely related to Drosophila M us101. We show that human TopBP1 is required for DNA replication and that i t interacts with DNA polymerase epsilon. In S phase TopBP1 colocalizes with Brca1 to foci that do not represent sites of ongoing DNA replication. Inhi bition of DNA synthesis leads to relocalization of TopBP1 together with Brc a1 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 Gi phase. We also show that TopBP1 interacts with t he checkpoint protein hRad9. Thus, these results implicate TopBP1 in replic ation and checkpoint functions.