Integrator restrains paraspeckles assembly by promoting isoform switching of the lncRNA NEAT1
Integrator restrains paraspeckles assembly by promoting isoform switching of the lncRNA NEAT1
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DOI：
10.1126/sciadv.aaz9072
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发表时间：
2020-07-01
期刊：
影响因子：
13.6
通讯作者：
Marine, Jean-Christophe
中科院分区：
文献类型：
--
作者：
Barra, Jasmine;Gaidosh, Gabriel S.;Marine, Jean-Christophe
RNA 3'端加工提供了影响各种（病理）生理过程的转录组多样化的来源。一个主要的例子是转录物同种型转换，其导致长的非编码RNA NEAT 1_2的通读表达，以较短的聚腺苷酸化转录物NEAT 1_1为代价。NEAT1_2是组装旁斑（PS）所必需的，旁斑是保护癌细胞免受癌基因诱导的复制应激和化疗的核体。寻找调节该事件的蛋白质，我们鉴定了参与聚腺苷酸化RNA的3'末端加工的因子和整合子复合物的组分。扰动实验证实，通过促进NEAT1_2的切割，Integrator迫使NEAT1_2转变为NEAT1_1同种型，从而抑制PS组装。一致地，低水平的整合子亚基与暴露于化疗药物的癌症患者的较差预后相关。我们的研究确定了Integrator调节PS生物发生以及Integrator、癌症生物学和化疗敏感性之间的联系，这可以用于治疗。
RNA 3' end processing provides a source of transcriptome diversification which affects various (patho)-physiological processes. A prime example is the transcript isoform switch that leads to the read-through expression of the long non-coding RNA NEAT1_2, at the expense of the shorter polyadenylated transcript NEAT1_1. NEAT1_2 is required for assembly of paraspeckles (PS), nuclear bodies that protect cancer cells from oncogene-induced replication stress and chemotherapy. Searching for proteins that modulate this event, we identified factors involved in the 3' end processing of polyadenylated RNA and components of the Integrator complex. Perturbation experiments established that, by promoting the cleavage of NEAT1_2, Integrator forces NEAT1_2 to NEAT1_1 isoform switching and, thereby, restrains PS assembly. Consistently, low levels of Integrator subunits correlated with poorer prognosis of cancer patients exposed to chemotherapeutics. Our study establishes that Integrator regulates PS biogenesis and a link between Integrator, cancer biology, and chemosensitivity, which may be exploited therapeutically.