Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation

Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2008; 283(12):7590-8. DOI: 10.1074/jbc.M709707200
Source: PubMed

ABSTRACT Werner syndrome is an autosomal recessive disorder associated with premature aging and cancer predisposition caused by mutations of the WRN gene. WRN is a member of the RecQ DNA helicase family with functions in maintaining genome stability. Sir2, an NAD-dependent histone deacetylase, has been proven to extend life span in yeast and Caenorhabditis elegans. Mammalian Sir2 (SIRT1) has also been found to regulate premature cellular senescence induced by the tumor suppressors PML and p53. SIRT1 plays an important role in cell survival promoted by calorie restriction. Here we show that SIRT1 interacts with WRN both in vitro and in vivo; this interaction is enhanced after DNA damage. WRN can be acetylated by acetyltransferase CBP/p300, and SIRT1 can deacetylate WRN both in vitro and in vivo. WRN acetylation decreases its helicase and exonuclease activities, and SIRT1 can reverse this effect. WRN acetylation alters its nuclear distribution. Down-regulation of SIRT1 reduces WRN translocation from nucleoplasm to nucleoli after DNA damage. These results suggest that SIRT1 regulates WRN-mediated cellular responses to DNA damage through deacetylation of WRN.

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    • "However, they also share the same target proteins. For instance, WRN and poly [ADP-ribose] polymerase 1 (PARP1) have been identified as target proteins of SIRT1 and SIRT6 [4] [5] [6] [7]. SIRT2 has been shown to regulate several targets of SIRT1 such as p65 and FOXO3 [8] [9] [10] [11]. "
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    Proteomics 07/2014; 14(13-14). DOI:10.1002/pmic.201400001 · 3.97 Impact Factor
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    • "SIRT1 can enhance DNA repair activity (Jeong et al., 2007; Li et al., 2008; Yuan et al., 2009; Dobbin et al., 2013) which could be attributed to SIRT1-induced deacetylation of histones and nonhistones , including histone H3 lysine 56 (H3K56) (Yuan et al., 2009), class I histone deacetylase (HDAC1) (Dobbin et al., 2013), Ku70 (Jeong et al., 2007), and WRN (Li et al., 2008). And the changes in both P16 and P21 can reflect the effects of SIRT1 on mediating age-related DNA damage of MSCs. "
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    Frontiers in Aging Neuroscience 06/2014; 6:103. DOI:10.3389/fnagi.2014.00103 · 2.84 Impact Factor
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    • "When a DSB occurs during S or G2 phases of the cell cycle, it will be preferentially repaired by homologous recombination (HR) using the sister chromatid as a template for DNA repair. SIRT1 modulates homologous recombination (HR) by deacetylating WRN –the gene mutated in the progeroid Werner Syndrome-and promoting its relocalization to DNA lesions (Li et al., 2008), where it repairs DNA strand breaks that arise from replication arrest. In this context, transgenic mice expressing increased levels of SIRT1 exhibit longer telomeres and higher frequency of sister chromatid HR events throughout the entire genome (Palacios et al., 2010). "
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