An ATR-independent checkpoint to monitor completion of DNA replication requires Rev7/Mad2L2

Cell cycle checkpoints have been identified that monitor all the critical steps during cell division, except for completion of DNA replication. Here we examined the hypothesis that Rev7/Mad2L2, a protein with sequence similarity to the Mad2 spindle assembly checkpoint protein, functions in a DNA replication completion checkpoint. In chicken and human cells, in which the ATR kinase was chemically inhibited, knockout of the REV7 gene allowed mitotic entry before DNA replication was completed. Mutants of Rev7 that could not homodimerize or that could not bind its ligands Rev3, the catalytic subunit of DNA polymerase zeta, and Champ1, a protein with ill-defined mitotic functions, lacked checkpoint function. Rev7 also underwent major conformational changes upon ligand binding, suggesting mechanistic similarities to the Mad2 spindle checkpoint. We propose that vertebrate Rev7 has an ATR-independent checkpoint function linking completion of DNA replication to mitotic entry.