美国哈佛大学Karen Adelman团队的最新研究揭示了整合酶缺失导致dsRNA形成，从而激活整合应激反应。2025年4月14日，国际知名学术期刊《细胞》发表了这一成果。
该课题组证明，在人类细胞中失去了介导的终止会触发综合应激反应（ISR）。INT耗竭会导致短基因如ISR转录因子激活转录因子3（ATF3）的上调。此外，未成熟的RNAPII在INT耗尽时逃逸到基因中，容易过早终止，产生不完整的带有保留内含子的pre-mRNAs。保留内含子内的逆转录因子形成双链RNA (dsRNA)，被蛋白激酶R（PKR）识别，从而驱动ATF4激活和延长ISR。关键的是，具有INT突变的患者细胞表现出dsRNA积累和ISR激活，从而暗示在由INT缺乏引起的疾病中存在慢性ISR。
据了解，整合酶（INT）是一种后生动物特异性复合物，针对启动子近端发病RNA聚合酶II （RNAPII）进行终止，阻止未成熟的RNAPII进入基因体，并在功能上减弱应激反应基因的转录。INT亚基突变与许多人类疾病有关，包括癌症、纤毛病和神经发育障碍，但INT活性降低如何导致疾病尚不清楚。
附：英文原文
Title: Integrator loss leads to dsRNA formation that triggers the integrated stress response
Author: Apoorva Baluapuri, Nicole ChenCheng Zhao, Ryan J. Marina, Kai-Lieh Huang, Anastasia Kuzkina, Maria E. Amodeo, Chad B. Stein, Lucie Y. Ahn, Jordan S. Farr, Ashleigh E. Schaffer, Vikram Khurana, Eric J. Wagner, Karen Adelman
Issue&Volume: 2025-04-14
Abstract: Integrator (INT) is a metazoan-specific complex that targets promoter-proximally paused RNA polymerase II (RNAPII) for termination, preventing immature RNAPII from entering gene bodies and functionally attenuating transcription of stress-responsive genes. Mutations in INT subunits are associated with many human diseases, including cancer, ciliopathies, and neurodevelopmental disorders, but how reduced INT activity contributes to disease is unknown. Here, we demonstrate that the loss of INT-mediated termination in human cells triggers the integrated stress response (ISR). INT depletion causes upregulation of short genes such as the ISR transcription factor activating transcription factor 3 (ATF3). Further, immature RNAPII that escapes into genes upon INT depletion is prone to premature termination, generating incomplete pre-mRNAs with retained introns. Retroelements within retained introns form double-stranded RNA (dsRNA) that is recognized by protein kinase R (PKR), which drives ATF4 activation and prolonged ISR. Critically, patient cells with INT mutations exhibit dsRNA accumulation and ISR activation, thereby implicating chronic ISR in diseases caused by INT deficiency.
DOI: 10.1016/j.cell.2025.03.025
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00343-5