Transcriptional silencing functions of the yeast protein Orc1/Sir3 subfunctionalized after gene duplication

Hickman, Meleah A.; Rusché, Laura N.

doi:10.1073/pnas.1006436107

Cited by 49 publications

(54 citation statements)

References 60 publications

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“…Orc1p and Sir3p are paralogs, and as such they display domain and primary sequence conservation, particularly in their N-terminal BAH domains (47% identical sequence). In Kluyveromyces lactis, Orc1p has been shown to function analogously to the role of Sir3 in heterochromatin formation, in addition to its traditional role in replication (41). We postulate that the binding interaction between SWI/SNF-family enzymes and Orc1-like BAH domains is ancestral and that specificity for Sir3p and Swi2p arose following the silencing subfunctionalization of Sir3p.…”

Section: Discussionmentioning

confidence: 98%

Direct interactions promote eviction of the Sir3 heterochromatin protein by the SWI/SNF chromatin remodeling enzyme

Manning

Peterson

2014

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

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Heterochromatin is a specialized chromatin structure that is central to eukaryotic transcriptional regulation and genome stability. Despite its globally repressive role, heterochromatin must also be dynamic, allowing for its repair and replication. In budding yeast, heterochromatin formation requires silent information regulators (Sirs) Sir2p, Sir3p, and Sir4p, and these Sir proteins create specialized chromatin structures at telomeres and silent mating-type loci. Previously, we found that the SWI/SNF chromatin remodeling enzyme can catalyze the ATP-dependent eviction of Sir3p from recombinant nucleosomal arrays, and this activity enhances early steps of recombinational repair in vitro. Here, we show that the ATPase subunit of SWI/SNF, Swi2p/Snf2p, interacts with the heterochromatin structural protein Sir3p. Two interaction surfaces are defined, including an interaction between the ATPase domain of Swi2p and the nucleosome binding, Bromo-AdjacentHomology domain of Sir3p. A SWI/SNF complex harboring a Swi2p subunit that lacks this Sir3p interaction surface is unable to evict Sir3p from nucleosomes, even though its ATPase and remodeling activities are intact. In addition, we find that the interaction between Swi2p and Sir3p is key for SWI/SNF to promote resistance to replication stress in vivo and for establishment of heterochromatin at telomeres.A ll eukaryotic genomes are stored within the nucleoprotein structure of chromatin, the core subunit of which, the nucleosome, consists of 147 base pairs (bp) of DNA wrapped ∼1.7 times around an octamer of histone proteins (1). Over millions of years, eukaryotes have incorporated chromatin structure into the regulation of many aspects of DNA metabolism, from simple nuclear packaging to transcriptional control (2). This diversity of purpose is reflected in two general types of chromatin structures within the nucleus-euchromatin, which is decondensed and transcriptionally active, and heterochromatin, which is typically localized to the nuclear periphery and repressive for DNA recombination and transcription. Heterochromatin structures are commonly associated with centromeres and telomeres, and these domains package much of a genome's repetitive DNA (3). Consequently, the maintenance of heterochromatin is key for genomic integrity, because it prevents illicit recombination among DNA repeats and promotes chromosome segregation during mitosis (4, 5).On a molecular level, heterochromatic loci are marked by specific chromatin posttranslational modifications, which are recognized and bound by characteristic nonhistone proteins. In many vertebrates, heterochromatin is characterized by members of the heterochromatin protein 1 (HP1) family of proteins, whereas in budding yeast, the silent information regulator (Sir) proteins, Sir2p, Sir3p, and Sir4p, create heterochromatin structures at telomeres and the silent mating-type loci (6, 7). Sir3p is believed to be the key structural component of yeast heterochromatin-Sir3p contains numerous protein-protein interaction motifs (8-10), incl...

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Section: Discussionmentioning

confidence: 98%

Direct interactions promote eviction of the Sir3 heterochromatin protein by the SWI/SNF chromatin remodeling enzyme

Manning

Peterson

2014

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

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“…Silencing was not a new function to the emergent SIR3 gene. ORC1 in the yeast Kluyveromyces lactis, which diverged from S. cerevisiae before genome duplication, functions in both DNA replication and transcriptional silencing (Hickman and Rusche 2010). The subfunctionalization of SIR3 and ORC1 has been substantial: S. cerevisiae Sir3 cannot replace Orc1 in DNA replication and Orc1 cannot replace Sir3 in silencing (Bell et al 1995).…”

Section: Evolutionary Considerations Of Sir3mentioning

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 keystone of these silencing proteins is the NAD + -dependent Sir2 histone deacetylase, which is responsible for deacetylating a number of lysines on the N-terminal tails of histones H3 and H4 (Imai et al 2000). Sir3 exhibits homology with the origin binding protein Orc1 and has a nucleosome binding BAH (bromo adjacent homology) domain Gallagher et al 2009;Hickman and Rusche 2010). None of the Sir proteins binds directly to DNA, but they interact with each other, with Sir3 and Sir4 directly interacting and Sir4 binding to Sir2 (Moazed et al 1997).…”

Section: Trans-acting Silencing Proteinsmentioning

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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Transcriptional silencing functions of the yeast protein Orc1/Sir3 subfunctionalized after gene duplication

Cited by 49 publications

References 60 publications

Direct interactions promote eviction of the Sir3 heterochromatin protein by the SWI/SNF chromatin remodeling enzyme

Direct interactions promote eviction of the Sir3 heterochromatin protein by the SWI/SNF chromatin remodeling enzyme

The Nuts and Bolts of Transcriptionally Silent Chromatin in Saccharomyces cerevisiae

Mating-Type Genes andMATSwitching inSaccharomyces cerevisiae

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