Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice.
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.
Wang
Rui-Hong
RH
Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Sengupta
Kundan
K
Li
Cuiling
C
Kim
Hyun-Seok
HS
Cao
Liu
L
Xiao
Cuiying
C
Kim
Sangsoo
S
Xu
Xiaoling
X
Zheng
Yin
Y
Chilton
Beverly
B
Jia
Rong
R
Zheng
Zhi-Ming
ZM
Appella
Ettore
E
Wang
Xin Wei
XW
Ried
Thomas
T
Deng
Chu-Xia
CX
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism / Q000528:radiation effects; D002478:Cells, Cultured; D043171:Chromosomal Instability; D004249:DNA Damage; D004260:DNA Repair; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D005865:Gestational Age; D006570:Heterochromatin / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000517:prevention & control; D000077185:Resveratrol; D056564:Sirtuin 1; D037761:Sirtuins / Q000032:analysis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D016588:Anticarcinogenic Agents; D006570:Heterochromatin; D006657:Histones; D013267:Stilbenes; D025521:Tumor Suppressor Proteins; C475961:gamma-H2AX protein, mouse; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol