Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation
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.
- SourceAvailable from: Namgyu Lee
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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    . SIRT2 has been shown to regulate several targets of SIRT1 such as p65 and FOXO3    . "
ABSTRACT: Sirtuins are NAD+-dependent deacetylases that regulate a range of cellular processes. Although diverse functions of sirtuins have been proposed, those functions of SIRT6 and SIRT7 which are mediated by their interacting proteins remain elusive. In the present study, we identified SIRT6- and SIRT7-interacting proteins, and compared their interactomes to investigate functional links. Our interactomes revealed 136 interacting proteins for SIRT6 and 233 for SIRT7 while confirming 7 and 111 proteins identified previously for SIRT6 and SIRT7, respectively. Comparison of SIRT6 and SIRT7 interactomes under the same experimental conditions disclosed 111 shared proteins, implying related functional links. The interaction networks of interactomes indicated biological processes associated with DNA repair, chromatin assembly and aging. Interactions of two highly acetylated proteins, nucleophosmin (NPM1) and nucleolin, with SIRT6 and SIRT7 were confirmed by co-immunoprecipitation. NPM1 was found to be deacetylated by both SIRT6 and SIRT7. In senescent cells, the acetylation level of NPM1 was increased in conjunction with decreased levels of SIRT6 and SIRT7, suggesting that the acetylation of NPM1 could be regulated by SIRT6 and SIRT7 in the aging process. Our comparative interactomic study of SIRT6 and SIRT7 implies important functional links to aging by their associations with interacting proteins.This article is protected by copyright. All rights reservedProteomics 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. "
ABSTRACT: Mesenchymal stem cells (MSCs) senescence is an age-related process that impairs the capacity for tissue repair and compromises the clinical use of autologous MSCs for tissue regeneration. Here, we describe the effects of SIRT1, a NAD(+)-dependent deacetylase, on age-related MSCs senescence. Knockdown of SIRT1 in young MSCs induced cellular senescence and inhibited cell proliferation whereas overexpression of SIRT1 in aged MSCs reversed the senescence phenotype and stimulated cell proliferation. These results suggest that SIRT1 plays a key role in modulating age-induced MSCs senescence. Aging-related proteins, P16 and P21 may be downstream effectors of the SIRT1-mediated anti-aging effects. SIRT1 protected MSCs from age-related DNA damage, induced telomerase reverse transcriptase (TERT) expression and enhanced telomerase activity but did not affect telomere length. SIRT1 positively regulated the expression of tripeptidyl peptidase 1 (TPP1), a component of the shelterin pathway that protects chromosome ends from DNA damage. Together, the results demonstrate that SIRT1 quenches age-related MSCs senescence by mechanisms that include enhanced TPP1 expression, increased telomerase activity and reduced DNA damage.Frontiers in Aging Neuroscience 06/2014; 6:103. DOI:10.3389/fnagi.2014.00103 · 2.84 Impact Factor
- "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). "
Article: Sirtuins, Metabolism, and Cancer[Show abstract] [Hide abstract]
ABSTRACT: More than a decade ago, sirtuins were discovered as a highly conserved family of NAD(+)-dependent enzymes that extend lifespan in lower organisms. In mammals, sirtuins are key regulators of stress responses and metabolism, influencing a range of diseases, including diabetes, neurodegeneration, and cancer. In recent years, new functions of sirtuins have been characterized, uncovering the underlying mechanisms of their multifaceted role in metabolism. Here, we specifically review recent progress on the role of sirtuins in DNA repair and energy metabolism, further discussing the implication of sirtuins in the biology of cancer.Frontiers in Pharmacology 02/2012; 3:22. DOI:10.3389/fphar.2012.00022 · 3.80 Impact Factor