SIRT1 is thought to underlie the link between caloric restriction and decreased cancer susceptibility. However, the role of mammalian SIRT1 in cancer is highly debated because of conflicting reports of its activity. Here, Wang et al. create a new mouse model in which the catalytic domain of SIRT1 is deleted, and no SIRT1 protein is expressed. They found that these mice have more severe phenotypes than other previously reported SIRT1 deletion models. SIRT1-null mice die before birth, and embryonic tissue analysis revealed that the SIRT1 deficiency leads to chromosome instability, impaired repair of DNA damage, and abnormal cell-cycle changes. Furthermore, Sirt1 heterozygotes have a significant increase in spontaneous tumor formation. The authors analyzed tumor cells from human clinical samples and reported that these cancer cells have decreased levels of SIRT1 expression. Taken as a whole, these studies of SIRT1 in mice and human tissue support the idea that SIRT1 acts as a positive regulator of tumor suppression.
Wang
R. H.
, Sengupta
K.
, Li
C.
, Kim
H. S.
, Cao
L.
, Xiao
C.
, Kim
S.
, Xu
X.
, Zheng
Y.
, Chilton
B.
, et al. . (2008
). Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice
. Cancer Cell
14
, 312
–323
.
