Gai Xiaochen, Xin Di, Wu Duo, Wang Xin, Chen Linlin, Wang Yiqing, Ma Kai, Li Qilin, Li Peng, Yu Xiaochun
Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
Cell Res. 2022 Mar;32(3):254-268. doi: 10.1038/s41422-021-00597-4. Epub 2022 Jan 4.
In response to DNA double-strand breaks (DSBs), DNA damage repair factors are recruited to DNA lesions and form nuclear foci. However, the underlying molecular mechanism remains largely elusive. Here, by analyzing the localization of DSB repair factors in the XY body and DSB foci, we demonstrate that pre-ribosomal RNA (pre-rRNA) mediates the recruitment of DSB repair factors around DNA lesions. Pre-rRNA exists in the XY body, a DSB repair hub, during meiotic prophase, and colocalizes with DSB repair factors, such as MDC1, BRCA1 and TopBP1. Moreover, pre-rRNA-associated proteins and RNAs, such as ribosomal protein subunits, RNase MRP and snoRNAs, also localize in the XY body. Similar to those in the XY body, pre-rRNA and ribosomal proteins also localize at DSB foci and associate with DSB repair factors. RNA polymerase I inhibitor treatment that transiently suppresses transcription of rDNA but does not affect global protein translation abolishes foci formation of DSB repair factors as well as DSB repair. The FHA domain and PST repeats of MDC1 recognize pre-rRNA and mediate phase separation of DSB repair factors, which may be the molecular basis for the foci formation of DSB repair factors during DSB response.
为响应DNA双链断裂（DSB），DNA损伤修复因子被招募至DNA损伤处并形成核灶。然而，其潜在的分子机制仍 largely难以捉摸。在此，通过分析DSB修复因子在XY体和DSB灶中的定位，我们证明前核糖体RNA（pre-rRNA）介导DSB修复因子在DNA损伤周围的招募。在减数分裂前期，pre-rRNA存在于作为DSB修复中心的XY体中，并与DSB修复因子共定位，如MDC1、BRCA1和TopBP1。此外，与pre-rRNA相关的蛋白质和RNA，如核糖体蛋白亚基、RNase MRP和snoRNAs，也定位在XY体中。与XY体中的情况类似，pre-rRNA和核糖体蛋白也定位在DSB灶处并与DSB修复因子相关联。RNA聚合酶I抑制剂处理可瞬时抑制rDNA转录但不影响整体蛋白质翻译，该处理消除了DSB修复因子的灶形成以及DSB修复。MDC1的FHA结构域和PST重复序列识别pre-rRNA并介导DSB修复因子的相分离，这可能是DSB反应期间DSB修复因子灶形成的分子基础。
