Mre11 protein complex prevents double-strand break accumulation during chromosomal DNA replication

Mre11 complex promotes repair of DNA double-strand breaks (DSBs). Xenopus M re11 (X-Mre11) has been cloned, and its role in DNA replication and DNA dam age checkpoint studied in cell-free extracts. DSBs stimulate the phosphoryl ation and 3'-5' exonuclease activity of X-Mre11 complex. This induced phosp horylation is ATM independent. Phosphorylated X-Mre11 is found associated w ith replicating nuclei. X-Mre11 complex is required to yield normal DNA rep lication products. Genomic DNA replicated in extracts immunodepleted of X-M re11 complex accumulates DSBs as demonstrated by TUNEL assay and reactivity to phosphorylated histone H2AX antibodies. In contrast, the ATM-dependent DNA damage checkpoint that blocks DNA replication initiation is X-Mre11 ind ependent. These results strongly suggest that the function of X-Mre11 compl ex is to repair DSBs that arise during normal DNA replication, thus unravel ing a critical link between recombination-dependent repair and DNA replicat ion.