BRAT1 links Integrator and defective RNA processing with neurodegeneration.
BRAT1 links Integrator and defective RNA processing with neurodegeneration.
复制标题
DOI：
10.1038/s41467-022-32763-6
复制
发表时间：
2022-08-26
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
编码BRCA 1相关ATM激活因子1的BRAT 1突变与神经发育和神经退行性疾病相关，其特征在于具有不同临床严重程度的异质性表型。然而，疾病病理学的潜在分子机制仍然知之甚少。在此，我们显示BRAT 1与整合子复合物的INTS 9/INTS 11亚基紧密相互作用，该复合物加工各种非编码RNA和前mRNA的3'端。我们发现，整合功能被破坏的BRAT 1删除。特别是，BRAT 1的缺陷阻碍了UsnRNA和snoRNA的正确3'端加工、复制依赖性组蛋白前mRNA加工，并改变了蛋白质编码基因的表达。重要的是，整合子功能的损伤在来自BRAT 1相关神经疾病的患者来源的细胞中也是明显的。总的来说，我们的数据表明BRAT 1的缺陷干扰了适当的整合子功能，导致RNA和蛋白质的不正确表达，从而导致神经退行性变。BRAT 1突变与神经发育迟缓和神经退行性变有关。在这里，作者表明BRAT 1是Integrator的一个组成部分，对于特定RNA的加工很重要。他们进一步证明，BRAT 1突变患者来源的细胞表现出整合子催化亚基水平降低和错误加工的UsnRNA水平升高以及RNA加工受损。
Mutations in BRAT1, encoding BRCA1-associated ATM activator 1, have been associated with neurodevelopmental and neurodegenerative disorders characterized by heterogeneous phenotypes with varying levels of clinical severity. However, the underlying molecular mechanisms of disease pathology remain poorly understood. Here, we show that BRAT1 tightly interacts with INTS9/INTS11 subunits of the Integrator complex that processes 3’ ends of various noncoding RNAs and pre-mRNAs. We find that Integrator functions are disrupted by BRAT1 deletion. In particular, defects in BRAT1 impede proper 3’ end processing of UsnRNAs and snoRNAs, replication-dependent histone pre-mRNA processing, and alter the expression of protein-coding genes. Importantly, impairments in Integrator function are also evident in patient-derived cells from BRAT1 related neurological disease. Collectively, our data suggest that defects in BRAT1 interfere with proper Integrator functions, leading to incorrect expression of RNAs and proteins, resulting in neurodegeneration. Mutations in BRAT1 are associated with neurodevelopmental delay and neurodegeneration. Here, the authors show that BRAT1 is a component of Integrator and is important for processing of specific RNAs. They further demonstrate that BRAT1 mutant patient-derived cells exhibit reduced levels of the Integrator catalytic subunit and increased levels of misprocessed UsnRNAs and impaired RNA processing.
登录
查看更多内容
DOI：
10.1074/mcp.m113.034769
发表时间：
2014-01
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Hebert AS;Richards AL;Bailey DJ;Ulbrich A;Coughlin EE;Westphall MS;Coon JJ
通讯作者：
Coon JJ
影响因子：
64.8
作者：
Lai F;Gardini A;Zhang A;Shiekhattar R
通讯作者：
Shiekhattar R
影响因子：
13.6
作者：
Barra, Jasmine;Gaidosh, Gabriel S.;Marine, Jean-Christophe
通讯作者：
Marine, Jean-Christophe
影响因子：
4.5
作者：
Gomez-Orte, Eva;Saenz-Narciso, Beatriz;Cabello, Juan
通讯作者：
Cabello, Juan
影响因子：
56.9
作者：
Edery, Patrick;Marcaillou, Charles;Leutenegger, Anne-Louise
通讯作者：
Leutenegger, Anne-Louise