The molecular basis of HORMAD2 functions in meiotic checkpoint control

在哺乳动物中，在第一次减数分裂期间正确的染色体分离要求同源染色体(同源)在第一次减数分裂前期通过联会复合体(SC)和随后的交叉(CO)联系在一起。共形成需要产生DNA双链断裂(DSB)，使用DSB末端进行同源搜索，并结合DSB修复形成SC。重要的是，必须防止减数分裂的进展，直到DSB修复和SC形成完成，以避免形成具有非整倍体或受损基因组的配子。人们对控制减数分裂进程的检查点知之甚少，尤其是监控SC形成的减数分裂特异性检查点。最近，我们发现HORMAD2是一种染色质相关蛋白，是两性减数分裂前期检查点机制的重要组成部分。重要的是，HORMAD2是消除SC缺陷卵母细胞所必需的。我们的数据表明，HORMAD2特定地参与了一个检查点，该检查点监测的是突触而不是未修复的DSB。HORMAD2是这种类型的第一种蛋白质。为了深入了解减数分裂前期检查点机制，我们建议通过遗传学(使用各种减数分裂缺陷突变体和我们的Hormad2突变体)和生物化学(HORMAD2相互作用和调节)来研究HORMAD2检查点功能的分子基础。鉴于非整倍体通常起源于人类的减数分裂前期错误，这项工作很可能对人类生殖生物学也有重要的影响。

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.