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Duo Wu^1,2,3, Huang Huang^1,2,3, Tenglong Chen^1,2,3

¹Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.

|October 3, 2023

概括

前核糖体RNA (pre-rRNA) 是DNA双链断裂 (DSB) 修复的关键合作伙伴,调解BRCA1/BARD1复合体的招募和功能. 这一发现揭示了DSB修复机制和潜在的癌症疗法.

科学领域:

分子生物学分子生物学
细胞生物学细胞生物学
遗传学是一个遗传学.

背景情况:

在体细胞和生殖细胞中,BRCA1/BARD1复合体对于DNA双链断裂 (DSB) 修复至关重要.
控制BRCA1/BARD1复杂介导的DSB修复的精确分子机制仍然不完全理解.
DSBs积聚在男性生殖细胞的XY体内,为研究修复提供了一个独特的背景.

研究的目的:

阐明BRCA1/BARD1复合体招募和功能在DSB修复中的分子机制.
研究前核糖体RNA (pre-rRNA) 在调解BRCA1/BARD1复合体活性中的作用.
探索前rRNA-BRCA1/BARD1相互作用对癌症和治疗敏感性的影响.

主要方法:

在男性生殖细胞中检查XY体,观察DSB积累和蛋白质定位.
生物化学测试以评估BRCA1/BARD1复合体和前rRNA之间的相互作用.
分析由BRCT域与前rRNA的相互作用诱导的液体-液体相分离.
在BRCA1/BARD1 BRCT域中研究与癌症相关的突变.
关于rRNA前生物发生抑制对细胞对PARP抑制剂敏感性的影响的研究.

主要成果:

将BRCA1/BARD1复合体招募到XY体的非突触轴上是由前rRNA介导的.
在体细胞中,BRCA1/BARD1复合体与前rRNA结合,形成DSB诱导的核点.
BRCA1/BARD1 BRCT域与前rRNA之间的相互作用会诱导液体-液体相分离,可能是潜在的焦点形成的基础.
在BRCA1/BARD1 BRCT域中与癌症相关的突变破坏了rRNA前结合.
前rRNA促进了BRCA1依赖的同源重组,其生物发生抑制提高了对PARP抑制剂的敏感性.

结论:

核糖体前RNA (pre-rRNA) 被确定为BRCA1/BARD1复合体在DNA双链断裂 (DSB) 修复中的功能合作伙伴.
预-rRNA通过涉及BRCT域和液态-液态相分离的相互作用,调解BRCA1/BARD1复合物的招募和向DSB.
这些发现揭示了pre-rRNA在DNA修复途径中的新作用,并表明了针对癌症治疗中的pre-rRNA生物发生的治疗意义.

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