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

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.
Cancer cell (Impact Factor: 23.52). 11/2008; 14(4):312-23. DOI: 10.1016/j.ccr.2008.09.001
Source: PubMed


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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Available from: Beverly S Chilton, Jan 13, 2014

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

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    • "SIRT1 has bifurcated roles in tumor progression. It inhibits tumor formation by improving genomic stability [39], but it induces tumor progression by promoting genomic instability, partially by inhibiting p53 through its deacetylation [40]. SIRT6 has common interacting partners with SIRT1, such as c-MYC, HIF1a, and NF-jB [2] [3] [4]. "
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    FEBS letters 07/2015; 589(17). DOI:10.1016/j.febslet.2015.06.043 · 3.17 Impact Factor
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    • "Classical gene targeting (GT) involves the replacement of an endogenous DNA fragment with an exogenously introduced DNA copy via homologous recombination (HR), which was first reported in yeast 30 years ago (Rothstein 1983). GT in embryonic stem (ES) cells followed by germline chimera formation is a routine in mice and has produced many mouse models available for the study of gene functions and genetic diseases (Capecchi 2005, Wang et al. 2008). A low HR frequency of ~10 −6 and dependence on ES cells have, however , limited this classic GT strategy to mouse (Capecchi 2005) and rat (Tong et al. 2010). "
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    ABSTRACT: Gene replacement (GR) via homologous recombination is a powerful tool for genome editing. Recently, direct GR is achieved successfully by coinjection of mRNAs for engineered endonucleases such as zinc finger nucleases (ZFNs) and donor DNA in developing embryos of diverse organisms. Here, we report the procedures and efficiency for direct GR by using ZFNs in the fish medaka. Upon zygotic coinjection of mRNAs encoding ZFNs that target the gonad-specifically expressed gsdf locus, linear DNA of GR vector pGRgsdf containing the red fluorescent protein (rfp) gene flanked by two homology arms of ~1-kb each underwent GR via homologous recombination. Specifically, 15 of 231 adults from manipulated embryos contained a GR allele in the caudal fin, producing an efficiency of ~7 % for somatic GR. Progeny test revealed that two out of nine fertile fish containing the GR allele in the fin were capable of transmitting the GR allele to ~6 % of F1 generation at adulthood, generating an efficiency of ~22 % for germline transmission. Sequencing and Southern blotting validated precise GR. We show that the GR allele expressed a chimeric gsdf:rfp RNA between gsdf and cointegrated rfp specifically in the gonad, demonstrating recapitulation of endogenous RNA expression as predicted for the defined GR allele. Most importantly, RFP expression coincides faithfully with the gonad-specific gsdf expression in developing embryos and adults. These results demonstrate, for the first time, the feasibility and efficiency of ZFN-mediated precise GR directly in the developing embryo of medaka as a lower vertebrate model.
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    • "SIRT1 has been reported to restrain LNCap cell proliferation [35]. Wang et al. demonstrated reduced SIRT1 expression in PCa tissue compared with in benign prostatic hyperplasia tissue [27]. SIRT1 can serve as a tumor promoter or tumor suppressor, depending on the oncogenic pathway specific to particular tumors [19],[22],[24]. "
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    ABSTRACT: Studies have shown that miR-221 and miR-222 are deregulated in many cancers, including prostate cancer. Nevertheless, the biological role and the underlying mechanisms of miR-221 and miR-222 in the pathogenesis of androgen-independent prostate cancer are still not clear. The proliferation, apoptosis, cell cycle distinction, and migration capacity of prostate cells were determined following transfection of miR-221 or miR-222 inhibitor. The biological impact and regulation of SIRT1 on prostate cancer cells were investigated. MiR-221 and miR-222 were highly expressed in PC-3 cells compared with in LNCap cells. After miR-221 or miR-222 expression was inhibited, the proliferation and migration rates of PC-3 cells decreased and the apoptosis rate increased. Moreover, SIRT1 protein was up-regulated in cells after they were transfected with miR-221 or miR-222 inhibitor. Cells transfected with siSIRT1 showed increased migration and a decreased apoptosis rate, but there was no significant effect on cell proliferation compared with the controls. There was a negative correlation between miR-221 or miR-222 and SIRT1, but no direct target relationship was identified. These data demonstrate that miR-221 and miR-222 are highly expressed in PC-3 cells. Their inhibition leads to reduced cell proliferation and migration and increased apoptosis in prostate cancer cells. These effects are potentially mediated by up-regulation of SIRT1.
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