Stabilization of Suv39H1 by SirT1 Is Part of Oxidative Stress Response and Ensures Genome Protection

Bosch-Presegué, Laia; Raurell‐Vila, Helena; Marazuela-Duque, Anna; Kane‐Goldsmith, Noriko; Valle, Adamo; Oliver, Jordi; Serrano, Lourdes; Vaquero, Alejandro

doi:10.1016/j.molcel.2011.02.034

Cited by 122 publications

(133 citation statements)

References 35 publications

(55 reference statements)

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“…However, SIRT1 is able to reverse this modification and elevate SUV39H1 activity by facilitating the interaction between the SET domain and the post-SET domain of SUV39H1 (18). In addition, SIRT1 inhibits MDM2-mediated ubiquitination and the subsequent degradation of SUV39H1 during oxidative stress, which, in turn, increases the turnover of SUV39H1 in heterochromatin and protects genome stability (19). In comparison with the acetyl group or the ubiquitin molecule, the methyl group is neutral and relatively smaller; therefore, methylation may influence SUV39H1 by other mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the phosphorylation of SUV39H1 during metaphase reinforces the association between SUV39H1 and the metaphase centromere (17). In addition, the deacetylation of SUV39H1 by silent mating type information regulation 2, homolog 1 (SIRT1) enhances SUV39H1 activity and facilitates heterochromatin formation (18), whereas the E3 ligase murine double minute 2, human homolog (MDM2)-mediated ubiquitination of SUV39H1 down-regulates SUV39H1 stability (19). Therefore, dissecting the potential PTMs of SUV39H1 in response to DNA damage may help us further understand the functions of SUV39H1.…”

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confidence: 99%

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Methylation of SUV39H1 by SET7/9 results in heterochromatin relaxation and genome instability

Wang

Zhou

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

103

106

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Suppressor of variegation 3-9 homolog 1 (SUV39H1), a histone methyltransferase, catalyzes histone 3 lysine 9 trimethylation and is involved in heterochromatin organization and genome stability. However, the mechanism for regulation of the enzymatic activity of SUV39H1 in cancer cells is not yet well known. In this study, we identified SET domain-containing protein 7 (SET7/9), a protein methyltransferase, as a unique regulator of SUV39H1 activity. In response to treatment with adriamycin, a DNA damage inducer, SET7/9 interacted with SUV39H1 in vivo, and a GST pull-down assay confirmed that the chromodomain-containing region of SUV39H1 bound to SET7/9. Western blot using antibodies specific for antimethylated SUV39H1 and mass spectrometry demonstrated that SUV39H1 was specifically methylated at lysines 105 and 123 by SET7/9. Although the half-life and localization of methylated SUV39H1 were not noticeably changed, the methyltransferase activity of SUV39H1 was dramatically down-regulated when SUV39H1 was methylated by SET7/ 9. Consequently, H3K9 trimethylation in the heterochromatin decreased significantly, which, in turn, led to a significant increase in the expression of satellite 2 (Sat2) and α-satellite (α-Sat), indicators of heterochromatin relaxation. Furthermore, a micrococcal nuclease sensitivity assay and an immunofluorescence assay demonstrated that methylation of SUV39H1 facilitated genome instability and ultimately inhibited cell proliferation. Together, our data reveal a unique interplay between SET7/9 and SUV39H1-two histone methyltransferases-that results in heterochromatin relaxation and genome instability in response to DNA damage in cancer cells.histone methylation | nonhistone posttranslational modifications

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Methylation of SUV39H1 by SET7/9 results in heterochromatin relaxation and genome instability

Wang

Zhou

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

103

106

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“…Microirradiation experiments and quantification of recruitment kinetics were performed following methods previously described (Hable et al , 2012) with some modifications. FRAP experiments were carried out as previously described (Bosch‐Presegue et al , 2011). …”

Section: Methodsmentioning

confidence: 99%

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

et al. 2016

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Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT7 targets acetylated lysine in the N‐terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT7 deletion is associated with reduced lifespan in mice through unknown mechanisms. Here, we show that SirT7‐knockout mice suffer from partial embryonic lethality and a progeroid‐like phenotype. Consistently, SIRT7‐deficient cells display increased replication stress and impaired DNA repair. SIRT7 is recruited in a PARP1‐dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53BP1 to DNA double‐strand breaks (DSBs), thereby influencing the efficiency of non‐homologous end joining (NHEJ). These results reveal a direct role for SIRT7 in DSB repair and establish a functional link between SIRT7‐mediated H3K18 deacetylation and the maintenance of genome integrity.

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“…To further elucidate the role of Sirt7 on Sirt1, we wanted to explore whether Sirt7 also controls other Sirt1 effects on heterochromatin. Interestingly, in an overexpression system, we observed that Sirt7 co-immunoprecipitates with the histone methyltransferase Suv39h1 (Figure 1(A)), which is bound and activated by Sirt1 [20,22] suggesting formation of a tripartite Sirt7/Sirt1/Suv39h1 complex. Co-immunoprecipitation experiments in primary mouse embryonic fibroblasts (MEFs) confirmed that endogenous Sirt7 and Suv39h1 form a molecular complex (Figure 1(B)).…”

Section: Resultsmentioning

confidence: 99%

Sirt7 inhibits Sirt1-mediated activation of Suv39h1

et al. 2018

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Sirtuins regulate a variety of cellular processes through protein deacetylation. The best-known member of mammalian sirtuin family, Sirt1, plays important roles in the maintenance of cellular homeostasis by regulating cell metabolism, differentiation and stress responses, among others. Sirt1 activity requires tight regulation to meet specific cellular requirements, which is achieved at different levels and by specific mechanisms. Recently, a regulatory loop between Sirt1 and another sirtuin, Sirt7, was identified. Sirt7 inhibits Sirt1 autodeacetylation at K230 and activation thereby preventing Sirt1-mediated repression of adipocyte differentiation by inhibition of the PPARγ gene. Here, we extend the regulatory complexity of Sirt7-dependent restriction of Sirt1 activity by demonstrating that Sirt7 reduces activation of a previously described prominent Sirt1 target, the histone methyltransferase Suv39h1. We show that removal of the acetyl-group at K230 in Sirt1 due to the absence of Sirt7 leads to hyperactivation of Sirt1 and thereby to constantly increased activity of Suv39h1.

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Stabilization of Suv39H1 by SirT1 Is Part of Oxidative Stress Response and Ensures Genome Protection

Cited by 122 publications

References 35 publications

Methylation of SUV39H1 by SET7/9 results in heterochromatin relaxation and genome instability

Methylation of SUV39H1 by SET7/9 results in heterochromatin relaxation and genome instability

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

Sirt7 inhibits Sirt1-mediated activation of Suv39h1

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