An uncertain silence

Sherman, Joyce M.; Pillus, Lorraine

doi:10.1016/s0168-9525(97)01198-0

Cited by 67 publications

(48 citation statements)

References 47 publications

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“…The study of the mechanism of silencing of these donors has occupied the attention of many labs and has provided some important insights into the way in which chromatin structure influences gene expression and recombination (see reviews by Laurenson and Rine 1992;Loo and Rine 1994;Sherman and Pillus 1997;Aström and Rine 1998;Rusche et al 2003;Hickman et al 2011). Our current understanding can be summarized as shown in Figure 4A.…”

Section: Silencing Of Hml and Hmrmentioning

confidence: 99%

Mating-Type Genes andMATSwitching inSaccharomyces cerevisiae

2012

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Mating type in Saccharomyces cerevisiae is determined by two nonhomologous alleles, MATa and MATa. These sequences encode regulators of the two different haploid mating types and of the diploids formed by their conjugation. Analysis of the MATa1, MATa1, and MATa2 alleles provided one of the earliest models of cell-type specification by transcriptional activators and repressors. Remarkably, homothallic yeast cells can switch their mating type as often as every generation by a highly choreographed, site-specific homologous recombination event that replaces one MAT allele with different DNA sequences encoding the opposite MAT allele. This replacement process involves the participation of two intact but unexpressed copies of mating-type information at the heterochromatic loci, HMLa and HMRa, which are located at opposite ends of the same chromosome-encoding MAT. The study of MAT switching has yielded important insights into the control of cell lineage, the silencing of gene expression, the formation of heterochromatin, and the regulation of accessibility of the donor sequences. Real-time analysis of MAT switching has provided the most detailed description of the molecular events that occur during the homologous recombinational repair of a programmed double-strand chromosome break. TABLE OF CONTENTS Abstract 33Introduction 34

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Section: Silencing Of Hml and Hmrmentioning

confidence: 99%

Mating-Type Genes andMATSwitching inSaccharomyces cerevisiae

2012

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“…The N-terminal deletion mutant (sir2-⌬N) was able to complement the sir2⌬ mating, HM, telomeric, and rDNA silencing defects as well as wild-type SIR2 on both high and low copy plasmids ( Figure 2B-D and our unpublished results). Thus, this nonconserved N-terminal region encompassing the first 79 amino acids of Sir2p is dispensable for mating-type silencing and does not promote the telomeric and rDNA silencing functions of SIR2 that are absent in HST1 (reviewed by Sherman and Pillus, 1997).…”

Section: The Core Of Sir2p Is Essential For Silencingmentioning

confidence: 99%

“…Sir2p is one of several factors critical for silencing at least three loci in yeast (reviewed by Loo and Rine, 1995;Sherman and Pillus, 1997). Among the four SIR (Silent Information Regulator) genes, SIR2 is unique because it is required for silencing and suppression of recombination within the rDNA, as well as silent mating-type (HM) and telomeric silencing (Shore et al, 1984;Ivy et al, 1986;Rine and Herskowitz, 1987;Gottlieb and Esposito, 1989;Aparicio et al, 1991;Bryk et al, 1997;Fritze and Esposito, 1997;Smith and Boeke, 1997;Smith et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…An hst3⌬ hst4⌬ double mutant exhibits telomeric silencing defects, as well as temperaturesensitive growth, cell cycle arrest, and chromosomal instability (Brachmann et al, 1995). The involvement of several of the HSTs in silencing has led to the hypothesis that they silence as yet unidentified loci in yeast and other organisms (Brachmann et al, 1995;Sherman and Pillus, 1997).…”

Section: Introductionmentioning

confidence: 99%

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The Conserved Core of a HumanSIR2Homologue Functions in Yeast Silencing

Sherman

Stone

Freeman-Cook

et al. 1999

MBoC

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Silencing is a universal form of transcriptional regulation in which regions of the genome are reversibly inactivated by changes in chromatin structure. Sir2 (Silent Information Regulator) protein is unique among the silencing factors in Saccharomyces cerevisiae because it silences the rDNA as well as the silent mating-type loci and telomeres. Discovery of a gene family of Homologues of Sir Two (HSTs) in organisms from bacteria to humans suggests that SIR2's silencing mechanism might be conserved. The Sir2 and Hst proteins share a core domain, which includes two diagnostic sequence motifs of unknown function as well as four cysteines of a putative zinc finger. We demonstrate by mutational analyses that the conserved core and each of its motifs are essential for Sir2p silencing. Chimeras between Sir2p and a human Sir2 homologue (hSir2Ap) indicate that this human protein's core can substitute for that of Sir2p, implicating the core as a silencing domain. Immunofluorescence studies reveal partially disrupted localization, accounting for the yeast-human chimeras' ability to function at only a subset of Sir2p's target loci. Together, these results support a model for the involvement of distinct Sir2p-containing complexes in HM/telomeric and rDNA silencing and that HST family members, including the widely expressed hSir2A, may perform evolutionarily conserved functions.

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“…Y east silent information regulator 2 (SIR2) protein functions in transcriptional silencing of the silent mating loci, telomeres, and rDNA (1)(2)(3). It is found in a chromatin-bound complex with SIR3 and SIR4 at the silent mating loci and telomeres, and in a different complex at rDNA (4)(5)(6).…”

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confidence: 99%

The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases

Landry

Sutton

Tafrov

et al. 2000

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

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878

647

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Homologs of the chromatin-bound yeast silent information regulator 2 (SIR2) protein are found in organisms from all biological kingdoms. SIR2 itself was originally discovered to influence mating-type control in haploid cells by locus-specific transcriptional silencing. Since then, SIR2 and its homologs have been suggested to play additional roles in suppression of recombination, chromosomal stability, metabolic regulation, meiosis, and aging. Considering the far-ranging nature of these functions, a major experimental goal has been to understand the molecular mechanism(s) by which this family of proteins acts. We report here that members of the SIR2 family catalyze an NAD-nicotinamide exchange reaction that requires the presence of acetylated lysines such as those found in the N termini of histones. Significantly, these enzymes also catalyze histone deacetylation in a reaction that absolutely requires NAD, thereby distinguishing them from previously characterized deacetylases. The enzymes are active on histone substrates that have been acetylated by both chromatin assemblylinked and transcription-related acetyltransferases. Contrary to a recent report, we find no evidence that these proteins ADPribosylate histones. Discovery of an intrinsic deacetylation activity for the conserved SIR2 family provides a mechanism for modifying histones and other proteins to regulate transcription and diverse biological processes.Y east silent information regulator 2 (SIR2) protein functions in transcriptional silencing of the silent mating loci, telomeres, and rDNA (1-3). It is found in a chromatin-bound complex with SIR3 and SIR4 at the silent mating loci and telomeres, and in a different complex at rDNA (4-6). Four additional SIR2 homologs exist in yeast (HST1-4), and related proteins are found from archaeabacteria to eubacteria to mammals (7). Until recently, very little was known about the in vivo activity of this family of proteins. An important breakthrough came with the identification of the Salmonella typhimurium CobB protein as a SIR2 homolog (8). CobB can partially fulfill the requirement for CobT in vitamin B 12 synthesis. Because CobT protein was known to transfer ribose 5Ј-phosphate from nicotinic acid mononucleotide to a precursor of vitamin B 12 , it prompted tests of Sir2-like proteins for phosphoribosyltransferase activity. Indeed, Frye (9) found that Escherichia coli CobB had NAD-dependent ADP-ribosyltransferase activity. He also reported that both CobB and a human SIR2-like protein could transfer radioactivity from [ 32 P]NAD to albumin. Very recently, another group (10) reported that yeast SIR2 can ADP-ribosylate itself as well as histones and albumin.Here we show that members of the SIR2 family of enzymes catalyze an NAD-nicotinamide exchange reaction that requires the presence of acetylated lysines such as are found in the N termini of histones. Furthermore, these enzymes also catalyze histone deacetylation in a reaction that absolutely depends on NAD, thereby distinguishing them from previously known deacet...

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An uncertain silence

Cited by 67 publications

References 47 publications

Mating-Type Genes andMATSwitching inSaccharomyces cerevisiae

Mating-Type Genes andMATSwitching inSaccharomyces cerevisiae

The Conserved Core of a HumanSIR2Homologue Functions in Yeast Silencing

The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases

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