Gcn5 and SAGA Regulate Shelterin Protein Turnover and Telomere Maintenance

Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA.
Molecular cell (Impact Factor: 14.02). 09/2009; 35(3):352-64. DOI: 10.1016/j.molcel.2009.06.015
Source: PubMed


Histone acetyltransferases (HATs) play important roles in gene regulation and DNA repair by influencing the accessibility of chromatin to transcription factors and repair proteins. Here, we show that deletion of Gcn5 leads to telomere dysfunction in mouse and human cells. Biochemical studies reveal that depletion of Gcn5 or ubiquitin-specific protease 22 (Usp22), which is another bona fide component of the Gcn5-containing SAGA complex, increases ubiquitination and turnover of TRF1, a primary component of the telomeric shelterin complex. Inhibition of the proteasome or overexpression of USP22 opposes this effect. The USP22 deubiquitinating module requires association with SAGA complexes for activity, and we find that depletion of Gcn5 compromises this association in mammalian cells. Thus, our results indicate that Gcn5 regulates TRF1 levels through effects on Usp22 activity and SAGA integrity.

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Available from: Làszlò Tora
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    • "It has been documented that a key regulator of cell cycle, p21, is regulated by USP22 [3], and depletion of USP22 results in a G1 phase cell-cycle arrest in human tumor cells [2]. Furthermore, USP22 participation in regulating shelterin protein turnover and telomere maintenance has also been demonstrated [4]. "
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    ABSTRACT: Ubiquitin-specific processing enzyme 22 (USP22) plays a direct role in regulating cell cycle, and its overexpression has been reported to be involved in tumor progression. However, little is known about the regulation of USP22 transcription. In this study, we cloned and characterized the human USP22 promoter. Using 5' RACE (rapid amplification of cDNA ends) analysis, the transcriptional initiation site was identified. Promoter deletion analysis showed that the sequence between -210 and -7 contains the basal promoter for USP22 in human fibroblast and tumor cells. Surprisingly, mutations in a putative Sp1 binding site immediately upstream of the USP22 transcriptional start site (-13 to -7) resulted in a significant induction of promoter activity. Further study revealed that Sp1 binds to this site in human normal fibroblast cells, and treatment with the Sp1 inhibitor mithramycin A led to a marked increase in USP22 transcript levels. Forced expression of exogenous Sp1 repressed the USP22 promoter activity in HeLa cells. In contrast, knockdown of Sp1 enhanced USP22 promoter activity and mRNA levels. These data suggest that Sp1 is a crucial regulator of USP22 transcription.
    Full-text · Article · Dec 2012 · PLoS ONE
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    • "Despite evidence about the function of USP22 in transcriptional regulation, cell-cycle progression and tumorigenesis, the mechanistic details of the way in which USP22 affects these processes remain unknown. We previously reported that USP22 participates in telomere maintenance by deubiquitinating nonhistone telomere-associated proteins, such as telomeric-repeatbinding factor 1 (TRF1) (Atanassov et al, 2009). Given this observation, we sought to explore whether USP22 regulates other cellular processes, by altering the ubiquitination level of other chromatin-associated substrates. "
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    ABSTRACT: Ubiquitin-specific protease 22 (USP22) edits the histone code by deubiquitinating H2A and H2B as part of the mammalian SAGA (Spt-Ada-Gcn5) complex, and is required for transcriptional regulation and normal cell-cycle progression. Here, we show that USP22 affects the expression of p21 by altering far upstream element (FUSE)-binding protein 1 (FBP1) ubiquitination, as ablation of USP22 leads to increased FBP1 ubiquitination and decreased FBP1 protein occupancy at the p21 gene. Surprisingly, increased polyubiquitination of FBP1 does not alter its protein stability, but instead modulates the stable recruitment of FBP1 to target loci. Our results indicate a mechanism by which USP22 regulates cell proliferation and tumorigenesis.
    Full-text · Article · Jul 2011 · EMBO Reports
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    • "In metazoans, Gcn5 exists in at least two HAT complexes including SAGA (Spt–Ada–Gcn5 acetyltransferase) and ATAC (Ada Two A containing) (Lee & Workman, 2007; Nagy & Tora, 2007). In addition to transcription regulation, Gcn5 is involved in diverse cellular processes such as DNA repair (Brand et al., 2001; Tamburini & Tyler, 2005), telomere maintenance (Atanassov et al., 2009), cell cycle progression (Orpinell et al., 2010; Paolinelli et al., 2009), and nucleosome assembly (Burgess et al., 2010). As a key catalytic component of the larger SAGA and ATAC complexes, Gcn5 preferentially acetylates lysines 9, 14, 27, and 56 of histone H3, and lysines 8 and 16 of H4 (Brownell et al., 1996; Burgess et al., 2010; Kuo et al., 1996; Tjeertes et al., 2009). "
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    ABSTRACT: Histone acetyltransferases (HATs) have a central role in the modification of chromatin as well as in the pathogenesis of a broad set of diseases including cancers. Gcn5 is the first identified transcription-related HAT that has been implicated in the regulation of diverse cellular functions. However, how Gcn5 proteins are regulated remains largely unknown. Here we show that acidic nucleoplasmic DNA-binding protein (And-1, a high mobility group domain-containing protein) has remarkable capability to regulate the stability of Gcn5 proteins and thereby histone H3 acetylation. We find that And-1 forms a complex with both histone H3 and Gcn5. Downregulation of And-1 results in Gcn5 degradation, leading to the reduction of H3K9 and H3K56 acetylation. And-1 overexpression stabilizes Gcn5 through protein-protein interactions in vivo. Furthermore, And-1 expression is increased in cancer cells in a manner correlating with increased Gcn5 and H3K9Ac and H3K56Ac. Thus, our data reveal not only a functional link between Gcn5 and And-1 that is essential for Gcn5 protein stability and histone H3 acetylation, but also a potential role of And-1 in cancer.
    Full-text · Article · Jul 2011 · Oncogene
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