The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage

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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.

Data availability

RNA-seq data has been deposited in GEO under accession number GSE118518.The Metadata sheets have been included as supplementary files

The following data sets were generated

1. Brady OA
2. Jeong E
3. Martina JA
4. Pirooznia M
5. Tunc I
6. Puertollano R
(2018) DNA Damage Response in control and TFEB/TFE3 double knockout cells treated with Etoposide
NCBI Gene Expression Omnibus, GSE118518.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE118518

Article and author information

Author details

Eutteum Jeong

Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Owen A Brady

Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Jose A Martina

Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Mehdi Pirooznia

Bioinformatics and Computational Biology Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Iker Tunc

Bioinformatics and Computational Biology Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Rosa Puertollano

Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States

For correspondence
puertolr@mail.nih.gov

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1106-5489

Funding

National Institutes of Health

Eutteum Jeong
Owen A Brady
Jose A Martina
Mehdi Pirooznia
Iker Tunc
Rosa Puertollano

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.