Ataxin-2 preserves oocyte genome integrity by promoting timely premeiotic DNA replication

The faithful reassortment and transmission of chromosomes across generations is fundamental to species survival. While much is known about chromosome pairing and recombination, the upstream regulators controlling entry into the meiotic program remain largely elusive. In many species, including Drosophila and mammals, the decision to enter meiosis occurs prior to premeiotic DNA replication and is governed by post-transcriptional regulation, by yet to be discovered factors. Here, we identify the RNA-binding protein Ataxin-2 as a crucial and previously unrecognized regulator of meiotic entry. We show that Ataxin-2 acts post-transcriptionally to promote the entry into meiosis by downregulating the conserved cell cycle inhibitor Dacapo, the Drosophila ortholog of p21/p27. In the absence of Ataxin-2, germ cells mis-regulate Dacapo leading to delayed premeiotic DNA replication and sterility. Strikingly, when DNA replication is delayed and extends into the next stage of meiosis, synaptonemal complex formation, oocytes incur severe genomic DNA damage, likely caused by collisions between replication forks and the synaptonemal complex. Our findings establish Ataxin-2 as a pivotal factor in regulating premeiotic DNA replication and safeguarding oocyte genome stability, shedding new light on the intricate regulatory mechanisms that ensure successful meiosis and fertility.