Genetic control of mitotic-to-meiotic transition regulates germline cell survival

Abstract

AO_SCPLOWBSTRACTC_SCPLOWThe coordination between DNA damage repair and cell cycle progression is essential to ensure cell survival and organ homeostasis. This is particularly critical during gametogenesis, where germline cells first proliferate and then transition from mitosis to meiosis. Meiotic cells frequently undergo recombination, which itself implies the generation of severe DNA damage in the form of double-strand DNA breaks (DSBs) that ought to be repaired to preserve genome integrity. Here, we identify Drosophila bru1 as an essential factor in the mitotic-to-meiotic transition in the female germline. The RNA-binding protein Bru1 is a translational repressor of multiple targets, including cyclins, and is sharply upregulated at the mitotic-to-meiotic boundary. We show that loss of bru1 disrupts germline development by altering cell cycle regulation, increasing DNA damage and cellular stress, and triggering apoptosis. bru1 mutants display clear signs of accelerated mitotic activity leading to extra divisions in the germline, in agreement with their elevated Cyclin A and B levels. Importantly, slowing cell cycle progression in bru1 mutants via string/cdc25 knockdown decreases DNA damage and cell death. Mechanistically, bru1 regulates mei-W68 transcription, the topoisomerase responsible for DSB production in the germline. Higher Mei-W68 levels induce premature and ectopic DSBs, which persist longer in the mutant germline, indicating defective repair and potentially resulting in p53-mediated apoptosis. Our work classifies bru1 as a safeguard of genome integrity and germline survival during the early stages of Drosophila female gametogenesis. bru1 regulates Mei-W68 levels and DSB formation, and controls the mitotic-to-meiotic transition by influencing cell cycle progression. The existence of bru1 homologues in mammals with established roles in gametogenesis suggests a broader biological relevance of our discoveries.