The molecular basis of HORMAD1 dependent coordination of key meiotic processes

关键减数分裂过程的 HORMAD1 依赖性协调的分子基础

• 批准号: 116471170
• 负责人: Professor Dr. Attila Tóth
• 金额: --
• 依托单位: Institut für Physiologische Chemie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/116471170?language=en
• 关键词: molecular; basis; HORMAD1; dependent; coordination

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.

同源染色体（同系物）之间的减数分裂交换（CO）的形成需要DNA双链断裂（DSB）的形成，使用DSB末端的同源性搜索，以及联会复合体（SC）的形成与DSB修复偶联。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。尽管它的重要性，减数分裂进程控制知之甚少。最近，我们确定HORMAD 1作为协调减数分裂进程和CO形成相关过程的核心参与者。HORMAD 1可确保有足够数量的已处理DSB可用于同源性搜索。正常SC形成需要HORMAD 1。最后，HORMAD 1在两种性别的减数分裂前期检查点中起关键作用，该功能可能通过招募和适应有丝分裂DNA损伤反应（DDR）蛋白来实现减数分裂特异性检查点功能。HOR-MAD 1是生殖系的关键监护人，因为HORMAD 1对于消除DSB修复缺陷和SC缺陷的卵母细胞至关重要。为了获得对减数分裂进程和CO相关减数分裂过程协调的新见解，我们将通过遗传学（使用DDR敲除和我们的Hormad 1-/-小鼠）和生物化学（HORMAD 1相互作用和调节）研究HORMAD 1功能的分子基础和DDR蛋白在HORMAD 1依赖性过程中的作用。鉴于非整倍体通常起源于人类减数分裂前期错误，这项工作将在人类生殖生物学方面具有重要意义。