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Updated: Feb 1, 2026
Describing a Transcription Factor Dependent Regulation of the MicroRNA Transcriptome
Published on: June 15, 2016
The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage
Owen A Brady1, Eutteum Jeong1, José A Martina1
1Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Maryland, United States.
Abstract:
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.
Insights
DNA damage activates transcription factors TFE3 and TFEB, crucial for the DNA damage response. These factors stabilize p53, regulate cell death, and control cell cycle checkpoints.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Transcription factors TFE3 and TFEB regulate autophagy and lysosome biogenesis.
- The role of TFE3 and TFEB in DNA damage response is not well understood.
Purpose of the Study:
- To investigate the role of TFE3 and TFEB in DNA damage response.
- To elucidate the mechanisms by which TFE3 and TFEB influence p53 stability and downstream pathways.
Main Methods:
- RNA-sequencing (RNA-Seq) analysis of TFEB/TFE3 double-knockout (DKO) cells.
- Etoposide treatment to induce DNA damage.
- Western blotting to assess protein levels and half-life.
Main Results:
- DNA damage activates TFE3 and TFEB in a p53 and mTORC1-dependent manner.
- TFEB/TFE3 DKO cells exhibit dysregulated DNA damage response, including altered p53 stability due to increased Mdm2 levels.
- TFE3 and TFEB depletion impairs lysosome membrane permeabilization and apoptosis induction.
- TFEB and TFE3 play a role in regulating cell cycle checkpoints under stress.
Conclusions:
- TFE3 and TFEB are critical regulators of the DNA damage response, influencing p53 stability, cell death pathways, and cell cycle control.
- These findings reveal a novel role for TFEB and TFE3 in maintaining genomic integrity and cellular homeostasis following DNA damage.
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