The Drosophila ATM homologue Mei-41 has an essential checkpoint function at the midblastula transition

Background: Drosophila embryogenesis is initiated by 13 rapid syncytial mit otic divisions that do not require zygotic gene activity. This maternally d irected cleavage phase of development terminates at the midblastula transit ion (MBT), at which point the cell cycle slows dramatically, membranes surr ound the cortical nuclei to form a cellular blastoderm, and zygotic gene ex pression is first required. Results: We show that embryos lacking Mei-41, a Drosophila homologue of the ATM tumor suppressor, proceed through unusually short syncytial mitoses, f ail to terminate syncytial division following mitosis 13, and degenerate wi thout forming cells. A similar cleavage-stage arrest is produced by mutatio ns in grapes, which encodes a homologue of the Checkpoint-1 kinase. We pres ent biochemical, cytological and genetic data indicating that Mei-41 and Gr apes are components of a conserved DNA-replication/damage checkpoint pathwa y that triggers inhibitory phosphorylation of the Cdc2 kinase and mediates resistance to replication inhibitors and DNA-damaging agents. This pathway is nonessential during postembryonic development, but it is required to ter minate the cleavage stage at the MBT. Cyclins are required for Cdc2 kinase activity, and mutations in cyclin A and cyclin B bypass the requirement for mei-41 at the MBT. These mutations do not restore wild-type syncytial cell -cycle timing or the embryonic replication checkpoint, however, suggesting that Mei-41-mediated inhibition of Cdc2 has an additional essential functio n at the MBT. Conclusions: The Drosophila DNA-replication/damage checkpoint pathway can b e activated by externally triggered DNA damage or replication defects throu ghout the life cycle, and under laboratory conditions this inducible functi on is nonessential. During early embryogenesis, however, this pathway is ac tivated by developmental cues and is required for the transition from mater nal to zygotic control of development at the MBT.