Impaired DNA Damage Response, Genome Instability, and Tumorigenesis in SIRT1 Mutant Mice

Rui Hong Wang, Kundan Sengupta, Cuiling Li, Hyun Seok Kim, Liu Cao, Cuiying Xiao, Sangsoo Kim, Xiaoling Xu, Yin Zheng, Beverly Chilton, Rong Jia, Zhi Ming Zheng, Ettore Appella, Xin Wei Wang, Thomas Ried, Chu Xia Deng

Research output: Contribution to journalArticlepeer-review

651 Scopus citations

Abstract

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 show that a majority of SIRT1 null embryos die between E9.5 and E14.5, displaying altered histone modification, impaired DNA damage response, and reduced ability to repair DNA damage. We demonstrate that Sirt1+/-;p53+/- mice develop tumors in multiple tissues, whereas activation of SIRT1 by resveratrol treatment reduces tumorigenesis. Finally, we show that many human cancers exhibit reduced levels of SIRT1 compared to normal controls. Thus, SIRT1 may act as a tumor suppressor through its role in DNA damage response and genome integrity.

Original languageEnglish
Pages (from-to)312-323
Number of pages12
JournalCancer Cell
Volume14
Issue number4
DOIs
StatePublished - 7 Oct 2008

Keywords

  • CELLCYCLE

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