Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses
Open accessAbstract
The mechanisms by which the p53 tumor suppressor acts remain incompletely understood. To gain new insights into p53 biology, we used high-throughput sequencing to analyze global p53 transcriptional networks in primary mouse embryo fibroblasts in response to DNA damage. Chromatin immunoprecipitation sequencing reveals 4785 p53-bound sites in the genome located near 3193 genes involved in diverse biological processes. RNA sequencing analysis shows that only a subset of p53-bound genes is transcriptionally regulated, yielding a list of 432 p53-bound and regulated genes. Interestingly, we identify a host of autophagy genes as direct p53 target genes. While the autophagy program is regulated predominantly by p53, the p53 family members p63 and p73 contribute to activation of this autophagy gene network. Induction of autophagy genes in response to p53 activation is associated with enhanced autophagy in diverse settings and depends on p53 transcriptional activity. While p53-induced autophagy does not affect cell cycle arrest in response to DNA damage, it is important for both robust p53-dependent apoptosis triggered by DNA damage and transformation suppression by p53. Together, our data highlight an intimate connection between p53 and autophagy through a vast transcriptional network and indicate that autophagy contributes to p53-dependent apoptosis and cancer suppression.
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The authors identified 20 targets related to autophagy activation and validated them by qPCR: ATG10, ATG14, ATG16L1, ATG3, ATG4, ATG7, ATG9A, BCL2, GABARAP, GABARAPL1, MAP1LC3B, NBR1, OPTN, PINK1, SQSTM1, ULK1, ULK2, UVRAG, WDR45, WIPI1.
“In a first case, starting from experimental data available in the literature, we identified 20 targets related to autophagy activation and validated them by qPCR: ATG10, ATG14, ATG16L1, ATG3, ATG4, ATG7, ATG9A, BCL2, GABARAP, GABARAPL1, MAP1LC3B, NBR1, OPTN, PINK1, SQSTM1, ULK1, ULK2, UVRAG, WDR45, WIPI1 (Fig. 2) [18–27].”
From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [24]
In “p53 binds to a host of autophagy genes” (page not provided), the source identifies several genes on the citing paper’s list, including ATG7, ATG10, ULK1, ULK2, and UVRAG, and reports qRT-PCR analyses of autophagy genes. It does not identify or report qPCR validation of the full set of 20. The citing sentence says “we” validated the targets, so that validation is the citing authors’ own work, not a finding attributed to this source. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe activation list was derived from comparison of publications reporting conditions of gene up-regulation upon autophagy activation.
“A so called “activation list” has been derived from the comparison of publications, in which we reported conditions of gene up-regulation upon autophagy activation [18–27].”
From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [24]
The restricted "induction list" for the prediction of autophagy activation state is made of 20 targets and was obtained by combining data from previous publications documenting increased mRNA expression following autophagy induction.
“The restricted “induction list” for the prediction of autophagy activation state, made by 20 targets, was obtained combining data from previous publications [18–27], in which have been documented the increase of the mRNA expression following autophagy induction.”
From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [24]
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- Authors
- Kenzelmann Broz, D., Spano Mello, S., Bieging, K. T., Jiang, D., Dusek, R. L., Brady, C. A., Sidow, A., & Attardi, L. D.
- Affiliations
- Stanford Medicine (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2013-05-01
- Volume
- 27
- Issue
- 9
- Pages
- 1016-1031
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3656320
- OpenAlex
- W2151607263
- Cited by
- 443
- References
- 13
- Citations by year
- 2026: 17 · 2025: 17 · 2024: 41 · 2023: 26 · 2022: 38 · 2021: 46 · 2020: 36 · 2019: 32 · 2018: 32 · 2017: 43 · 2016: 41 · 2015: 31 · 2014: 30 · 2013: 12 · 2012: 1
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- American Cancer Society
- Leukemia and Lymphoma Society
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- National Cancer Institute (T32CA009151, CA140875, R01CA140875)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- p53, autophagy, p53 target genes, DNA damage response, p63, p73, p53-dependent apoptosis, cell cycle arrest, tumor suppression, mouse embryonic fibroblasts, ChIP-seq, RNA sequencing
- MeSH terms
- Animals, Autophagy, Cell Survival, Cells, Cultured, DNA Damage, Embryo, Mammalian, Fibroblasts, Protein Binding, Up-Regulation, Tumor Suppressor Protein p53, Sequence Analysis, RNA, Gene Expression Regulation, Developmental, Mice, Genome-Wide Association Study, Cell Cycle Checkpoints
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