The molecular basis of HORMAD1 dependent coordination of key meiotic processes

同源染色体之间的减数分裂交叉(CO)形成包括DNA双链断裂(DSB)形成、利用DSB末端进行同源搜索和联会复合体(SC)形成与DSB修复相结合。必须防止减数分裂进程，直到DSB修复和SC形成完成，以避免形成具有异常基因组的配子。尽管减数分裂进程控制很重要，但人们对它知之甚少。最近，我们发现HORMAD1在协调减数分裂进程和CO形成相关过程中起着中心作用。HORMAD1确保有足够数量的处理过的DSB可用于同源搜索。正常的SC形成需要HORMAD1。最后，HORMAD1在两性的减数分裂前期检查点中发挥关键作用，这一功能可能是通过招募和调整有丝分裂DNA损伤反应(DDR)蛋白来实现减数分裂特定检查点功能的。HOR-MAD1是生殖系的关键守护者，因为HORMAD1对于消除DSB修复缺陷和SC缺陷卵母细胞都是必不可少的。为了对减数分裂进程和CO相关减数分裂过程的协调有新的见解，我们将从遗传学(使用DDR基因敲除和我们的Hormad1-/-小鼠)和生物化学(HORMAD1相互作用和调控)研究HORMAD1功能的分子基础和DDR蛋白在HORMAD1依赖过程中的作用。鉴于非整倍体通常起源于人类的减数分裂前期错误，这项工作也将对人类生殖生物学产生重要的影响。

Meiotic crossover (CO) formation between homologous chromosomes (homologues) entails DNA double strand break (DSB) formation, homology search using DSB ends, and synaptonemal complex (SC) formation coupled with DSB repair. Meiotic progression must be prevented until DSB repair and SC formation are completed to avoid formation of gametes with abnormal genomes. Despite its im-portance, meiotic progression control is poorly understood. Recently, we identified HORMAD1 as a central player in the coordination of meiotic progression and CO formation associated processes. HORMAD1 ensures that sufficient numbers of processed DSBs are available for homology search. HORMAD1 is needed for normal SC formation. Finally, HORMAD1 plays a critical role in meiotic pro-phase checkpoints in both sexes, a function that is probably performed through recruiting and adapt-ing mitotic DNA damage response (DDR) proteins for meiosis specific checkpoint functions. HOR-MAD1 is a key guardian of the germline, since HORMAD1 is essential for the elimination of both DSB repair- and SC-defective oocytes. To gain novel insights into the coordination of meiotic progression and CO associated meiotic processes, we will study the molecular basis of HORMAD1 functions and the role of DDR proteins in HORMAD1 dependent processes trough genetics (using DDR knockout and our Hormad1-/- mice) and biochemistry (HORMAD1 interactions and regulation). Given that an-euploidies often originate from meiotic prophase errors in humans this work will have important impli-cations in human reproductive biology as well.