Loss of Drp1 induces replication stress-mediated genome instability. Loss of Drp1 induces replication stress-mediated genome instability. Our working model shows that mitochondrial hyperfusion that is induced by loss of the fission protein Drp1 leads to replication stress, centrosome overduplication, and chromosomal instability. These are mediated, at least in part, by the aberrant expression of cyclin E in the G2-phase. Persistent replication stress activates an ATM kinase signaling cascade that induces a G2/M cell cycle checkpoint. This is consistent with our data, which show that knockdown of the fusion protein Opa1, cyclin E or ATM reverses the G2/M cell cycle arrest and aneuploidy observed in Drp1-deficient cells. ATR kinase is essential for DNA damage responses to replication stress. Loss of Drp1 induces replication stress, which is further increased by the loss of ATR. This subsequently increases DNA damage and cell death. Wei Qian et al. J Cell Sci 2012;125:5745-5757 © 2012. Published by The Company of Biologists Ltd