The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
Impaired DNA Damage Response, Genome Instability, and Tumorigenesis in SIRT1 Mutant Mice
Open accessAbstract
Summary In lower eukaryotes, Sir2 serves as a histone deacetylase and is implicated in chromatin silencing, longevity and genome stability. Here we mutated the SIRT1 gene, a homolog of yeast Sir2, in mice to study its function. We showed that a majority of SIRT1-null embryos died between E9.5–E14.5, displaying altered histone modification, impaired DNA damage response, and reduced ability to repair DNA damage. We demonstrated that SIRT1+/−;p53+/− mice developed tumors in multiple tissues, whereas activation of SIRT1 by resveratrol treatment reduced tumorigenesis. Finally, we showed that many human cancers exhibited reduced level of SIRT1 than their normal controls. Thus, SIRT1 acts as a tumor suppressor through its role in DNA damage response, genome integrity, and tumor suppression. Significance SIRT1 has diverse roles in various biological processes, including caloric restriction that causes changes in glucose metabolism and lifespan. The role of SIRT1 in cancer is currently under debate due to some recent different findings. It is known that calorie restriction, which activates SIRT1, extends lifespan and inhibits tumorigenesis. On the other hand, SIRT1 deacetylates p53 to decrease its activity. It was therefore hypothesized increased SIRT1 activity, although it extends lifespan, may elevate cancer risk. Here we demonstrate SIRT1 plays an important role in DNA damage response and genome integrity by maintaining proper chromatin structure and DNA damage repair foci formation. We further show that SIRT1 serves as a tumor suppressor in mice and in some types of human cancers.
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Cites
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Cited by
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982
Mammalian Sirtuins: Biological Insights and Disease Relevance
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Cantó, C., Menzies, K. J., & Auwerx, J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.023 · Cited by 1,648
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential
Xie, N., Zhang, L., Gao, W., Huang, C., Huber, P. E., Zhou, X., Li, C., Shen, G., & Zou, B. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00311-7 · Cited by 1,052
Self-citationKim, H.-S., Patel, K., Muldoon-Jacobs, K., Bisht, K. S., Aykin-Burns, N., Pennington, J. D., van der Meer, R., Nguyen, P., Savage, J., Owens, K. M., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2009.11.023 · Cited by 785
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Metadata
- Authors
- Wang, R.-H., Sengupta, K., Li, C., Kim, H.-S., Cao, L., Xiao, C., Kim, S., Xu, X., Zheng, Y., Chilton, B., Jia, R., Zheng, Z.-M., Appella, E., Wang, X. W., Ried, T., & Deng, C.-X.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 14
- Issue
- 4
- Pages
- 312-323
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2037723157
- Cited by
- 769
- References
- 51
- FWCI
- 18.21
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Wang, R.-H., Sengupta, K., Li, C., Kim, H.-S., Cao, L., Xiao, C., Kim, S., Xu, X., Zheng, Y., Chilton, B., Jia, R., Zheng, Z.-M., Appella, E., Wang, X. W., Ried, T., & Deng, C.-X. (2008). Impaired DNA Damage Response, Genome Instability, and Tumorigenesis in SIRT1 Mutant Mice. Cancer Cell. https://doi.org/10.1016/j.ccr.2008.09.001
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