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.
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.
Rui-Hong
RH
Wang
Kundan
K
Sengupta
Cuiling
C
Li
Hyun-Seok
HS
Kim
Liu
L
Cao
Cuiying
C
Xiao
Sangsoo
S
Kim
Xiaoling
X
Xu
Yin
Y
Zheng
Beverly
B
Chilton
Rong
R
Jia
Zhi-Ming
ZM
Zheng
Ettore
E
Appella
Xin Wei
XW
Wang
Thomas
T
Ried
Chu-Xia
CX
Deng
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