Repression by Ume6 Involves Recruitment of a Complex Containing Sin3 Corepressor and Rpd3 Histone Deacetylase to Target Promoters

Kadosh, David; Struhl, Kevin

doi:10.1016/s0092-8674(00)80217-2

Cited by 513 publications

(510 citation statements)

References 34 publications

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“…Ume6 exerts control of transcription by forming a complex with the corepressor Sin3 and the histone deacetylase Rpd3 (15). Accordingly, we extended our analysis by examining the level of Atg8 in rpd3Δ and sin3Δ strains.…”

Section: Resultsmentioning

confidence: 94%

Ume6 transcription factor is part of a signaling cascade that regulates autophagy

Bartholomew

Suzuki

et al. 2012

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

100

123

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Autophagy has been implicated in a number of physiological processes important for human heath and disease. Autophagy involves the formation of a double-membrane cytosolic vesicle, an autophagosome. Central to the formation of the autophagosome is the ubiquitin-like protein autophagy-related (Atg)8 (microtubuleassociated protein 1 light chain 3/LC3 in mammalian cells). Following autophagy induction, Atg8 shows the greatest change in expression of any of the proteins required for autophagy. The magnitude of autophagy is, in part, controlled by the amount of Atg8; thus, controlling Atg8 protein levels is one potential mechanism for modulating autophagy activity. We have identified a negative regulator of ATG8 transcription, Ume6, which acts along with a histone deacetylase complex including Sin3 and Rpd3 to regulate Atg8 levels; deletion of any of these components leads to an increase in Atg8 and a concomitant increase in autophagic activity. A similar regulatory mechanism is present in mammalian cells, indicating that this process is highly conserved.lysosome | membrane biogenesis | phagophore | stress | vacuole M acroautophagy, hereafter referred to as autophagy, is an evolutionarily conserved process used by eukaryotic cells for the bulk degradation of intracellular proteins and organelles (1). Autophagy is not only vital for cell survival in nutrient-poor conditions (2) but is also linked to various physiological processes, including immune defense, tumor suppression, and prevention of neurodegeneration (3). Whereas autophagy plays a primarily protective role, it can also contribute to cell death; thus, the magnitude of autophagy must be carefully regulated.Central to autophagy is the formation of autophagosomes (4), double-membrane-bound structures that engulf and deliver cytoplasmic materials to the vacuole/lysosome for degradation. During autophagosome formation, the autophagy-related ubiquitin-like protein Atg8/microtubule-associated protein 1 light chain 3 (LC3) covalently modifies phosphatidylethanolamine (PE). Almost one-fourth of the characterized autophagy-related (Atg) proteins in yeast are involved in the formation or stability of Atg8-PE, which plays a critical role in controlling expansion of the phagophore (the initial sequestering membrane), and in determining autophagosome size, thereby regulating autophagy activity (5, 6). Upon starvation, the level of ATG8 mRNA sharply increases, leading to a subsequent induction of the Atg8 protein level (7,8). The increase in the amount of Atg8 during autophagy is critical for supplying a sufficient amount of this protein to maintain normal levels of autophagy; yeast strains deficient in Atg8 induction generate abnormally small autophagosomes (5). Thus, characterization of how Atg8 protein levels are modulated is of tremendous importance both in understanding the regulation of autophagy and for the elucidation of potential therapeutic targets. However, little is known about the mechanisms regulating ATG8 transcription. ResultsUme6-Sin3-Rpd3 Complex Represse...

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Section: Resultsmentioning

confidence: 94%

Ume6 transcription factor is part of a signaling cascade that regulates autophagy

Bartholomew

Suzuki

et al. 2012

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

100

123

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“…Previous work has shown that these factors interact with other proteins to form a heterogeneous multiprotein complex of Ͼ1 MDa that is recruited to the promoters of target genes by the DNA-binding protein Ume6p (26)(27)(28). The deacetylase activity of Rpd3p then results in the formation of a localized domain of hypoacetylated chromatin that is thought to inhibit transcription by preventing the recruitment of the transcriptional machinery (29)(30)(31)(32). Significantly, genomewide localization studies have revealed that, apart from residing on the promoter regions of its target genes, the Sin3p͞Rpd3p complex also binds to nonpromoter sequences independently of Ume6p.…”

mentioning

confidence: 99%

Saccharomyces cerevisiae Sin3p facilitates DNA double-strand break repair

Jazayeri

McAinsh

Jackson

2004

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

148

114

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There are two main pathways in eukaryotic cells for the repair of DNA double-strand breaks: homologous recombination and nonhomologous end joining. Because eukaryotic genomes are packaged in chromatin, these pathways are likely to require the modulation of chromatin structure. One way to achieve this is by the acetylation of lysine residues on the N-terminal tails of histones. Here we demonstrate that Sin3p and Rpd3p, components of one of the predominant histone deacetylase complexes of Saccharomyces cerevisiae, are required for efficient nonhomologous end joining. We also show that lysine 16 of histone H4 becomes deacetylated in the proximity of a chromosomal DNA doublestrand break in a Sin3p-dependent manner. Taken together, these results define a role for the Sin3p͞Rpd3p complex in the modulation of DNA repair.I n eukaryotic cells, the genome is compacted into chromatin.The basic unit of chromatin is the nucleosome, which is composed of the conserved core histones H2A, H2B, H3, and H4. The structure of nucleosomal DNA is further compacted by a range of other factors, including proteins such as the linker histone H1 that binds to DNA between the nucleosome repeats (1). Various DNA-templated processes such as transcription, replication, and DNA repair take place in the context of chromatin and so must involve the manipulation of nucleosomes. One way to achieve this is through the reversible acetylation, phosphorylation, ubiquitination, or ADP-ribosylation of the histone tails that extend to the accessible surface of the nucleosome core particle (2). It has been proposed that combinations of these modifications create a ''histone code'' that is recognized by other proteins to bring about specific downstream events (3).The most extensive body of data has been accumulated for the effect of nucleosome modifications in transcription (4). However, there is growing evidence that there is cross-talk between chromatin and DNA damage response and repair pathways. This is particularly well established for nucleotide excision repair (NER), in which several chromatin remodeling and modification factors have been implicated (ref. 5 and references therein). As discussed further below, there is also evidence for the importance of chromatin modification in the repair of DNA doublestrand breaks (DSBs), which are generated by ionizing radiation and a range of chemotherapeutic agents. Given the highly recombinogenic and cytotoxic nature of such lesions (6, 7), the impact of chromatin on DSB repair is likely to be of considerable biological importance.There are two principle mechanisms for the repair of DNA DSBs: homologous recombination (HR) and nonhomologous end joining (NHEJ). The former requires genes in the RAD52 epistasis group and relies on extensive homology between the damaged DNA and an undamaged partner [sister chromatid or homologous chromosome (8)]. By contrast, NHEJ requires little or no homology between the recombining molecules (9). Key components of the NHEJ machinery in mammals include the Ku70͞Ku80 heterodimer an...

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“…Based on the ideas about the function of the SNF/SWI complex, the simplest model for explaining the defect of nps1-105 in meiotic gene activation is that Nps1p is required for recruiting the Ime1p-Ume6p complex on URS1 sites or in converting a negative regulatory complex formed on the URS1 site through Ume6p to a positive Ime1p-Ume6p complex. Recent studies by Kadosh & Struhl (1997) and Kasten et al (1997) have shown that Ume6p forms a huge complex with Sin3p, Rpd3p and possibly with some other proteins when it functions as a repressor. The starvation of a/␣ cells stimulates IME1 expression and Ime1p then converts Ume6p to activator with Rim11p, while the mechanism of this conversion is unclear.…”

Section: Discussionmentioning

confidence: 99%

Nps1/Sth1p, a component of an essential chromatin‐remodeling complex of Saccharomyces cerevisiae, is required for the maximal expression of early meiotic genes

et al. 1999

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Repression by Ume6 Involves Recruitment of a Complex Containing Sin3 Corepressor and Rpd3 Histone Deacetylase to Target Promoters

Cited by 513 publications

References 34 publications

Ume6 transcription factor is part of a signaling cascade that regulates autophagy

Ume6 transcription factor is part of a signaling cascade that regulates autophagy

Saccharomyces cerevisiae Sin3p facilitates DNA double-strand break repair

Nps1/Sth1p, a component of an essential chromatin‐remodeling complex of Saccharomyces cerevisiae, is required for the maximal expression of early meiotic genes

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