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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.

SUBMITTER: Wang RH

PROVIDER: S-EPMC2643030 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice.

Wang Rui-Hong RH 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

Cancer cell 20081001 4

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 act ...[more]

PMID: 18835033

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Project description:Minichromosome maintenance proteins (Mcm's) are components of the DNA replication licensing complex. In vivo, reduced expression or activity of Mcm's has been shown to result in highly penetrant early onset cancers (Shima et al., 2007; Pruitt et al., 2007) and stem cell deficiencies (Pruitt et al., 2007). Here we use mouse embryonic fibroblasts from an Mcm2-deficient strain of mice to show by DNA fiber analysis that origin usage is decreased in Mcm2-deficient cells under conditions of hydroxyurea (HU)-mediated replication stress. DNA damage responses (DDRs) resulting from HU and additional replication-dependent and replication-independent genotoxic agents were also examined and shown to function at wild-type (wt) levels. Further, basal levels of many components of the DDR were expressed at wt levels, showing that there is no acute replicative stress under normal growth conditions. Only very modest, 1.5- to 2-fold increases in the basal levels of gamma-H2AX, p21(cip1) and 53bp foci were found, consistent with a slight chronic elevation in DDR pathways. The one condition in which a larger difference between wt- and Mcm2-deficient cells was found occurred after ultraviolet irradiation and may reflect the role of Chk1-mediated suppression of dormant origins. In vivo, abrogating p53-mediated DDR in Mcm2-deficient mice results in increased embryonic lethality and accelerated cancer formation in surviving mice. Further, p53 mutation rescues the negative effect of Mcm2 deficiency on the survival of neural stem cells in vitro; however, the enhanced survival correlates with increased genetic damage relative to Mcm2 wt cells carrying the p53 mutation. Together these results show that even relatively minor perturbations to primary or dormant replication origin usage contribute to accelerated genetic damage in vivo. In addition, these studies show that tumor types resulting from Mcm2 deficiency are strongly affected by interaction with both genetic background and p53.

Project description:Parental exposure to environmental stress can result in an increased diseases risk in the offspring. Although literature on maternal contribution to hereditary diseases are growing, the paternal contribution is frequently underrecognized. Since human studies reported that 80% of transmitted mutations arise in the paternal germline, it is crucial to understand the mechanism underlying the paternally inherited genome instability. Ionizing radiation (IR) is a major source of mutagenesis through inducing DNA double-strand breaks (DSBs). Here, we used sex-separated C. elegans mutants to investigate the paternal contribution to IR-induced transgenerational effects. Specifically, we found that paternal exposure to IR leads to a transgenerational embryonic lethality, and this effect is only observed when the radiation exposure occurred close to the time of fertilization. In the offspring of the irradiated males (F1 generation), we detected various genome instability phenotypes, including DNA fragmentation, chromosomal rearrangement, and aneuploidy. These phenotypes are attributed to the usage of two error-prone repair machinery, the polymerase-theta mediated end joining (TMEJ) and the non-homologous End Joining (NHEJ). Surprisingly, depletion of a human histone H1.0 ortholog, HIS-24, can significantly rescue this transgenerational embryonic lethality. Moreover, this rescue effect is associated with the downregulation of heterochromatin marker histone 3 lysine 9 di-methylation (H3K9me2), and the knocking-down of heterochromatin protein, HPL-1, could mimic the rescue effect of HIS-24 depletion. We also noticed that removal of the histone H1 and heterochromatin marker could activate the error-free repair machinery, Homologous Recombination repair (HR), thus improving the viability of the offspring carrying paternally inherited DNA damage. Altogether, our work sheds light on the importance of paternal radiation exposure on the health of offspring. In addition, our work establishes a previously unknown mechanism underlying the transgenerational genome instability and provides a potential therapeutic target for preventing the hereditary diseases caused by paternal radiation exposure.

Dataset Information

Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice.

Publications

Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice.

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