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

doi:10.1016/j.ccr.2008.09.001

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

Department of Life Science

Research output: Contribution to journal › Article › peer-review

696 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 language	English
Pages (from-to)	312-323
Number of pages	12
Journal	Cancer Cell
Volume	14
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2008.09.001
State	Published - 7 Oct 2008

Bibliographical note

Funding Information:
We thank members of the Deng laboratory for critical discussions of this work. We gratefully acknowledge H.M. Padilla-Nash and N. McNeil for assistance with SKY analyses. This research was supported by the Intramural Research Program of the NIH National Institute of Diabetes and Digestive and Kidney Diseases.

Keywords

CELLCYCLE

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10.1016/j.ccr.2008.09.001

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

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.",

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note = "Funding Information: We thank members of the Deng laboratory for critical discussions of this work. We gratefully acknowledge H.M. Padilla-Nash and N. McNeil for assistance with SKY analyses. This research was supported by the Intramural Research Program of the NIH National Institute of Diabetes and Digestive and Kidney Diseases. ",

year = "2008",

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doi = "10.1016/j.ccr.2008.09.001",

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AU - Wang, Rui Hong

AU - Sengupta, Kundan

AU - Li, Cuiling

AU - Kim, Hyun Seok

AU - Cao, Liu

AU - Xiao, Cuiying

AU - Kim, Sangsoo

AU - Xu, Xiaoling

AU - Zheng, Yin

AU - Chilton, Beverly

AU - Jia, Rong

AU - Zheng, Zhi Ming

AU - Appella, Ettore

AU - Wang, Xin Wei

AU - Ried, Thomas

AU - Deng, Chu Xia

N1 - Funding Information: We thank members of the Deng laboratory for critical discussions of this work. We gratefully acknowledge H.M. Padilla-Nash and N. McNeil for assistance with SKY analyses. This research was supported by the Intramural Research Program of the NIH National Institute of Diabetes and Digestive and Kidney Diseases.

PY - 2008/10/7

Y1 - 2008/10/7

N2 - 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.

AB - 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.

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DO - 10.1016/j.ccr.2008.09.001

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SN - 1535-6108

VL - 14

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EP - 323

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -

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

Abstract

Bibliographical note

Keywords

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