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.

RNA 3' 末端加工提供了转录组多样化的来源，影响各种（病理）生理过程。一个主要的例子是转录本异构体开关，它导致长非编码 RNA NEAT1_2的通读表达，但代价是较短的聚腺苷酸化转录本NEAT1_1。NEAT1_2是副斑点 (PS) 组装所必需的，副斑点是保护癌细胞免受癌基因诱导的复制应激和化疗影响的核体。为了寻找调节这一事件的蛋白质，我们确定了参与多聚腺苷酸化 RNA 3' 端加工和整合复合物成分的因子。扰动实验表明，通过促进NEAT1_2的裂解，Integrator 迫使NEAT1_2向NEAT1_1同工型转换，从而抑制 PS 组装。一致地，低水平的整合子亚基与接受化疗的癌症患者的较差预后相关。我们的研究证实 Integrator 调节 PS 生物发生以及 Integrator、癌症生物学和化学敏感性之间的联系，这可能在治疗上得到利用。