RMI2 regulates recombination intermediate metabolism to ensure proper chromosome segregation in mammalian meiosis

Abstract

Abstract Proper segregation of meiotic chromosomes depends on the controlled formation and resolution of recombination intermediates that give rise to crossovers (COs). While the BTRR complex—comprising the BLM helicase, topoisomerase IIIα, and the proteins RMI1 and RMI2—is a well-characterized regulator of recombination in somatic cells, its function during meiosis remains incompletely understood, particularly for RMI2 in mammals. Here, we investigate the role of RMI2 in mouse spermatogenesis using a targeted RMI2 knockout model. Loss of RMI2 results in severe meiotic defects, including reduced testis size, increased apoptosis at the metaphase–anaphase I transition, and frequent chromosomal abnormalities such as lagging chromosomes in metaphase I cells and anaphase I chromatin bridges. Cytological analyses reveal disruptions in the processing of recombination intermediates. Our work monitoring molecular recombination outcomes at known recombination hotspots suggests that RMI2 regulates the balance of recombination pathways, constrains aberrant branch migration, and ensures proper CO maturation. Our findings show previously unappreciated functions for RMI2 essential for coordinating recombination intermediate metabolism and promoting proper chromosome conformation and segregation during meiosis. These results provide insights into the complex regulation of recombination intermediate homeostasis in higher eukaryotes and highlight the role of RMI2 in maintaining genome stability and proper gamete development in mammals.