The Cyclin-dependent kinase inhibitor Dacapo promotes genomic stability during premeiotic S phase.
The proper execution of premeiotic S phase is essential to both the maintenance of genomic integrity and accurate chromosome segregation during the meiotic divisions. However, the regulation of premeiotic S phase remains poorly defined in metazoa. Here, we identify the p21(Cip1)/p27(Kip1)/p57(Kip2)-like cyclin-dependent kinase inhibitor (CKI) Dacapo (Dap) as a key regulator of premeiotic S phase and genomic stability during Drosophila oogenesis. In dap(-/-) females, ovarian cysts enter the meiotic cycle with high levels of Cyclin E/cyclin-dependent kinase (Cdk)2 activity and accumulate DNA damage during the premeiotic S phase. High Cyclin E/Cdk2 activity inhibits the accumulation of the replication-licensing factor Doubleparked/Cdt1 (Dup/Cdt1). Accordingly, we find that dap(-/-) ovarian cysts have low levels of Dup/Cdt1. Moreover, mutations in dup/cdt1 dominantly enhance the dap(-/-) DNA damage phenotype. Importantly, the DNA damage observed in dap(-/-) ovarian cysts is independent of the DNA double-strands breaks that initiate meiotic recombination. Together, our data suggest that the CKI Dap promotes the licensing of DNA replication origins for the premeiotic S phase by restricting Cdk activity in the early meiotic cycle. Finally, we report that dap(-/-) ovarian cysts frequently undergo an extramitotic division before meiotic entry, indicating that Dap influences the timing of the mitotic/meiotic transition.
Narbonne-Reveau
Karine
K
Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Lilly
Mary
M
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D019927:Cyclin E / Q000037:antagonists & inhibitors; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000378:metabolism*; D005260:Female; D042822:Genomic Instability; D008540:Meiosis; D050505:Mutant Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D009865:Oocytes / Q000166:cytology / Q000201:enzymology; D010053:Ovary / Q000166:cytology / Q000201:enzymology; D010641:Phenotype; D016196:S Phase; D013194:Staining and Labeling; D013573:Synaptonemal Complex / Q000201:enzymology
D018797:Cell Cycle Proteins; D019927:Cyclin E; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D004268:DNA-Binding Proteins; C411983:DUP protein, Drosophila; D029721:Drosophila Proteins; D050505:Mutant Proteins; D009687:Nuclear Proteins; C103336:dap protein, Drosophila; D051357:Cyclin-Dependent Kinase 2; C495887:cdk2 protein, Drosophila