The molecular basis of HORMAD2 functions in meiotic checkpoint control

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In mammals, correct chromosome segregation during the first meiotic division requires that homologous chromosomes (homologues) become linked by the synaptonemal complex (SC) and subsequently by crossovers (CO) during the first meiotic prophase. CO formation entails generation of DNA double strand breaks (DSBs), homology search using DSB ends and SC formation coupled with DSB repair. Crucially, meiotic progression must be prevented until DSB repair and SC formation are completed to avoid formation of gametes with aneuploid or damaged genomes. The checkpoints controlling meiotic progression are little understood, especially the meiosis specific checkpoints that monitor SC formation. Recently, we identified HORMAD2 as a chromatin associated protein that is a crucial component of meiotic prophase checkpoint mechanisms in both sexes. Importantly, HORMAD2 is required for the elimination of SC-defective oocytes. Our data suggest that HORMAD2 is specifically involved in a checkpoint that monitors asynapsis rather than unrepaired DSBs. HORMAD2 is the first protein of this kind. To gain insight into the poorly understood meiotic prophase checkpoint mechanisms, we propose to study the molecular basis of HORMAD2 checkpoint functions through genetics (using various meiosis defective mutants and our Hormad2 mutant) and biochemistry (HORMAD2 interactions and regulation). Given that aneuploidies often originate from meiotic prophase errors in humans this work is likely to have important implications in human reproductive biology as well.