Bypassing Sir2 and O-Acetyl-ADP-Ribose in Transcriptional Silencing

Chou, Chia-Ching; Li, Yao-Cheng; Gartenberg, Marc R.

doi:10.1016/j.molcel.2008.06.020

Cited by 35 publications

(36 citation statements)

References 42 publications

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“…Interestingly, a recent study reported apparently OAADPRindependent silencing by a fusion protein between the NAD + -independent HDAC Hos3 and Sir3 (40). One explanation to reconcile this observation with our data is that OAADPR is required for the interaction and recruitment of Sir2/Sir4 to Sir3.…”

Section: Discussionsupporting

confidence: 85%

Rpd3-dependent boundary formation at telomeres by removal of Sir2 substrate

Ehrentraut

Weber

Dybowski

et al. 2010

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

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Boundaries between euchromatic and heterochromatic regions until now have been associated with chromatin-opening activities. Here, we identified an unexpected role for histone deacetylation in this process. Significantly, the histone deacetylase (HDAC) Rpd3 was necessary for boundary formation in Saccharomyces cerevisiae . rpd3 Δ led to silent information regulator (SIR) spreading and repression of subtelomeric genes. In the absence of a known boundary factor, the histone acetyltransferase complex SAS-I, rpd3 Δ caused inappropriate SIR spreading that was lethal to yeast cells. Notably, Rpd3 was capable of creating a boundary when targeted to heterochromatin. Our data suggest a mechanism for boundary formation whereby histone deacetylation by Rpd3 removes the substrate for the HDAC Sir2, so that Sir2 no longer can produce O-acetyl-ADP ribose (OAADPR) by consumption of NAD + in the deacetylation reaction. In essence, OAADPR therefore is unavailable for binding to Sir3, preventing SIR propagation.

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Section: Discussionsupporting

confidence: 85%

Rpd3-dependent boundary formation at telomeres by removal of Sir2 substrate

Ehrentraut

Weber

Dybowski

et al. 2010

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

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“…A binding site for the metabolite has yet to be defined within the Sir2/3/4 complex. To test whether OAADPr was essential for silencing and whether other deacetylases could substitute for Sir2, silent chromatin was assembled in vivo with Hos3, an Rpd3-family deacetylase that neither consumes NAD nor produces OAADPr (Chou et al 2008). Hos3 was targeted to assembling silent chromatin domains by creating a Sir3-Hos3 fusion protein.…”

Section: Lessons Learned From Silent Chromatin Reconstitutionmentioning

confidence: 99%

The Nuts and Bolts of Transcriptionally Silent Chromatin in Saccharomyces cerevisiae

2016

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Transcriptional silencing in Saccharomyces cerevisiae occurs at several genomic sites including the silent mating-type loci, telomeres, and the ribosomal DNA (rDNA) tandem array. Epigenetic silencing at each of these domains is characterized by the absence of nearly all histone modifications, including most prominently the lack of histone H4 lysine 16 acetylation. In all cases, silencing requires Sir2, a highly-conserved NAD + -dependent histone deacetylase. At locations other than the rDNA, silencing also requires additional Sir proteins, Sir1, Sir3, and Sir4 that together form a repressive heterochromatin-like structure termed silent chromatin. The mechanisms of silent chromatin establishment, maintenance, and inheritance have been investigated extensively over the last 25 years, and these studies have revealed numerous paradigms for transcriptional repression, chromatin organization, and epigenetic gene regulation. Studies of Sir2-dependent silencing at the rDNA have also contributed to understanding the mechanisms for maintaining the stability of repetitive DNA and regulating replicative cell aging. The goal of this comprehensive review is to distill a wide array of biochemical, molecular genetic, cell biological, and genomics studies down to the "nuts and bolts" of silent chromatin and the processes that yield transcriptional silencing.

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“…The effect was dramatic with the Sir2,3,4p complex, but is also quite significant with Sir3p alone, suggesting that it is the key target (Martino et al 2009). The evidence against this hypothesis is based on a Sir3p-Hos3 fusion protein used to demonstrate that telomeric silencing can occur in the absence of O-AADPR (Chou et al 2008). Hos3 is an NAD + -independent deacetylase that does not produce O-AADPR, nor does it normally deacetylate histones.…”

Section: O-aadprmentioning

confidence: 99%

“…Hos3 is an NAD + -independent deacetylase that does not produce O-AADPR, nor does it normally deacetylate histones. When fused in-frame to the C terminus of Sir3p, it deacetylates histones at silent loci as measured by ChIP, and this effectively silences DNA (Chou et al 2008). However, while it does not silence as well as wildtype yeast, it does silence as well as a Sir3-Sir2p fusion protein (Chou et al 2008).…”

Section: O-aadprmentioning

confidence: 99%

Silent information regulator 3: the Goldilocks of the silencing complex

Norris

Boeke²

2010

Genes Dev.

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A recent explosion of work surrounds the interactions between Sir3p (Silent Information Regulator 3) and chromatin. We review here the Sir3p functions related to its role in silencing in Saccharomyces cerevisiae. This unusual protein, which is absolutely required for silencing, is distantly related to the highly conserved replication initiator Orc1p, but is itself phylogenetically limited to “post-genome-duplicated” budding yeasts. Several recent studies revise earlier models for Sir3p action. Specifically, the N-terminal bromo-adjacent homology (BAH) domain plays a now well-defined role in silencing, and a picture is emerging in which both termini of Sir3p bind two locations on the nucleosome: (1) the loss of ribosomal DNA silencing (LRS) surface in the nucleosome core, and (2) the N-terminal histone tails for effective silencing at telomeres. We relate Sir3p structure and function, and summarize recent molecular studies of Sir3p/chromatin binding, Sir3p/Dot1p competition, and the possible role of O-Acetyl ADP ribose (O-AADPR) in Sir3p/chromatin binding. We emphasize recent genetic data that provide important new insights and settle controversies created by in vitro work. Finally, we synthesize these ideas to revise the model for how Sir3p mediates silent chromatin formation in yeast, in part through its affinity for the LRS region of the nucleosome, which must be “just right.”

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Bypassing Sir2 and O-Acetyl-ADP-Ribose in Transcriptional Silencing

Cited by 35 publications

References 42 publications

Rpd3-dependent boundary formation at telomeres by removal of Sir2 substrate

Rpd3-dependent boundary formation at telomeres by removal of Sir2 substrate

The Nuts and Bolts of Transcriptionally Silent Chromatin in Saccharomyces cerevisiae

Silent information regulator 3: the Goldilocks of the silencing complex

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