The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage
The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage
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DOI：
10.7554/elife.40856
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发表时间：
2018-12-06
期刊：
影响因子：
7.7
通讯作者：
Puertollano, Rosa
中科院分区：
文献类型：
--
作者：
Jeong, Eutteum;Brady, Owen A.;Puertollano, Rosa
转录因子TFE3和TFEB协同调节自噬诱导和溶酶体的生物发生以响应饥饿。在这里，我们证明了DNA损伤激活TFE3和TFEB的方式依赖于p53和mTORC1。对暴露于依托泊苷的TFEB/TFE3双敲除细胞的RNA-Seq分析显示，DNA损伤反应存在严重的失调，包括上游调节因子和下游p53靶标。TFE3和TFEB通过稳定P53蛋白水平来维持P53依赖的反应。在TFEB/TFE3 DKO中，由于MDM2水平升高，P53半衰期显著缩短。在TFEB/TFE3缺失的细胞中，参与溶酶体膜通透性和细胞死亡途径的基因的转录谱是不受调控的。因此，长时间的DNA损伤会导致LMP受损，并诱导细胞凋亡。最后，在TFEB/TFE3 DKO中，与细胞周期控制有关的多个基因的表达发生了变化，揭示了TFEB和TFE3在调节细胞周期检查点以响应压力方面的先前未知的作用。
The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.