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SIRT4 Has Tumor-Suppressive Activity and Regulates the Cellular Metabolic Response to DNA Damage by Inhibiting Mitochondrial Glutamine Metabolism
Open accessAbstract
DNA damage elicits a cellular signaling response that initiates cell cycle arrest and DNA repair. Here, we find that DNA damage triggers a critical block in glutamine metabolism, which is required for proper DNA damage responses. This block requires the mitochondrial SIRT4, which is induced by numerous genotoxic agents and represses the metabolism of glutamine into tricarboxylic acid cycle. SIRT4 loss leads to both increased glutamine-dependent proliferation and stress-induced genomic instability, resulting in tumorigenic phenotypes. Moreover, SIRT4 knockout mice spontaneously develop lung tumors. Our data uncover SIRT4 as an important component of the DNA damage response pathway that orchestrates a metabolic block in glutamine metabolism, cell cycle arrest, and tumor suppression.
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“Moreover, evidence has shown that during the DNA damage response, normal cells show a decrease in glutaminolysis controlled by SIRT4 protein suppressing GLUD1. In the absence of SIRT4, a failure to undergo cell cycle arrest induced by DNA damage causes a delay in DNA repair and increased chromosomal instability, suggesting a tumor suppressor effect of SIRT4151.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [151]
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“Accordingly, loss of SIRT4 enhances glutamine-dependent proliferation and genomic instability, which simultaneously contribute to tumorigenesis151.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [151]
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“Similarly, SIRT4 is upregulated as part of the DNA damage response via ATF4 (Jeong et al. 2013).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Jeong et al. 2013
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“SIRT4 likewise appears to control tumorigenesis ((Jeong et al. 2013), (Csibi et al. 2013)) by inhibiting the high rate of glutamine metabolism associated with cancer growth;”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Jeong et al. 2013
In the citing paper
“DHODH activity is also elevated in response to DNA damage and upon genotoxic chemotherapy treatment to increase nucleotide synthesis for DNA repair.76,77”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [76]
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Metadata
- Authors
- Jeong, S. M., Xiao, C., Finley, L. W. S., Lahusen, T., Souza, A. L., Pierce, K., Li, Y.-H., Wang, X., Laurent, G., German, N. J., Xu, X., Li, C., Wang, R.-H., Lee, J., Csibi, A., Cerione, R., Blenis, J., Clish, C. B., Kimmelman, A., Deng, C.-X., & Haigis, M. C.
- Affiliations
- Harvard University (US)
- National Institutes of Health (US)
- Broad Institute (US)
- Cornell University (US)
- Corresponding author
- Deng, Chu-Xia
- Haigis, Marcia C.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 23
- Issue
- 4
- Pages
- 450-463
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3650305
- OpenAlex
- W2046120998
- Cited by
- 445
- References
- 56
- Citations by year
- 2026: 9 · 2025: 31 · 2024: 27 · 2023: 28 · 2022: 33 · 2021: 43 · 2020: 42 · 2019: 31 · 2018: 41 · 2017: 32 · 2016: 41 · 2015: 38 · 2014: 24 · 2013: 23
- FWCI
- 19.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG032375, AG032375)
- National Cancer Institute (R01CA157490)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- SIRT4, DNA damage response, glutamine metabolism, mitochondrial metabolism, TCA cycle, tumor suppression, genomic instability, cell cycle arrest, lung cancer, genotoxic stress, tumor suppressor
- MeSH terms
- Animals, DNA Damage, DNA Repair, Female, Glutamine, Humans, Male, Mitochondria, Neoplasms, Experimental, Signal Transduction, Mice, Knockout, Mitochondrial Proteins, Tumor Suppressor Proteins, Sirtuins, Cell Line, Tumor, Cell Growth Processes, Mice, Hep G2 Cells, HEK293 Cells
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