On the Mechanism of Gene Silencing in <i>Saccharomyces cerevisiae</i>

Steakley, David Lee; Rine, Jasper

doi:10.1534/g3.115.018515

Cited by 14 publications

(23 citation statements)

References 54 publications

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“…For example, in humans, regions of constitutive heterochromatin are typically enriched for H3K9 trimethylation, whereas regions of facultative heterochromatin such as those found in inactivated X chromosomes and at loci that regulate cell identity are typically enriched for H3K27 trimethylation (1,2). Despite the range of mechanisms and proteins involved in heterochromatin formation and maintenance, certain characteristics appear universal and underlie a fundamental relationship between heterochromatin structure and function: Heterochromatin is structurally compact, localizes to distinct areas of the nucleus, and promotes transcriptional repression by limiting access of RNA polymerases to DNA (3)(4)(5)(6)(7)(8)(9)(10). The replication and epigenetic inheritance of heterochromatin are enigmatic in at least three ways.…”

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confidence: 99%

Pivotal roles of PCNA loading and unloading in heterochromatin function

Janke

King

Kupiec

et al. 2018

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

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In , heterochromatin structures required for transcriptional silencing of the and loci are duplicated in coordination with passing DNA replication forks. Despite major reorganization of chromatin structure, the heterochromatic, transcriptionally silent states of and are successfully maintained throughout S-phase. Mutations of specific components of the replisome diminish the capacity to maintain silencing of and through replication. Similarly, mutations in histone chaperones involved in replication-coupled nucleosome assembly reduce gene silencing. Bridging these observations, we determined that the proliferating cell nuclear antigen (PCNA) unloading activity of Elg1 was important for coordinating DNA replication forks with the process of replication-coupled nucleosome assembly to maintain silencing of and through S-phase. Collectively, these data identified a mechanism by which chromatin reassembly is coordinated with DNA replication to maintain silencing through S-phase.

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confidence: 99%

Pivotal roles of PCNA loading and unloading in heterochromatin function

Janke

King

Kupiec

et al. 2018

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

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“…eterochromatin-based gene silencing in Saccharomyces cerevisiae and its close relatives among the budding yeasts use the four Sir proteins to bind to nucleosomes throughout specific regions on chromosomes and to block the accessibility of other DNA binding proteins in that region (1)(2)(3). In these species, the Sir1 protein is perhaps most enigmatic.…”

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Evolution and Functional Trajectory of Sir1 in Gene Silencing

Ellahi

Rine

2016

Molecular and Cellular Biology

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We used the budding yeasts Saccharomyces cerevisiae and Torulaspora delbrueckii to examine the evolution of Sir-based silencing, focusing on Sir1, silencers, the molecular topography of silenced chromatin, and the roles of SIR and RNA interference (RNAi) genes in T. delbrueckii. Chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) analysis of Sir proteins in T. delbrueckii revealed a different topography of chromatin at the HML and HMR loci than was observed in S. cerevisiae. S. cerevisiae Sir1, enriched at the silencers of HML␣ and HMRa, was absent from telomeres and did not repress subtelomeric genes. In contrast to S. cerevisiae SIR1's partially dispensable role in silencing, the T. delbrueckii SIR1 paralog KOS3 was essential for silencing. KOS3 was also found at telomeres with T. delbrueckii Sir2 (Td-Sir2) and Td-Sir4 and repressed subtelomeric genes. Silencer mapping in T. delbrueckii revealed single silencers at HML and HMR, bound by Td-Kos3, Td-Sir2, and Td-Sir4. The KOS3 gene mapped near HMR, and its expression was regulated by Sir-based silencing, providing feedback regulation of a silencing protein by silencing. In contrast to the prominent role of Sir proteins in silencing, T. delbrueckii RNAi genes AGO1 and DCR1 did not function in heterochromatin formation. These results highlighted the shifting role of silencing genes and the diverse chromatin architectures underlying heterochromatin.

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“…In the standard model for silencing, once nucleated at the silencers, Sir2 deacetylates the H3 and H4 tails on the neighboring nucleosome, allowing the Sir-protein complex to bind to the hypoacetylated nucleosome. Iterative rounds of deacetylation lead to the spreading of Sir protein complexes across the silenced loci, resulting in silencing at HML and HMR (Hoppe et al 2002;Rusché et al 2002) largely by occluding transcription factors (Loo and Rine 1994;Steakley and Rine 2015;Wang et al 2015). The nucleation and spreading model makes the simple prediction that, although Sir2's catalytic activity is necessary, it should be bypassed by the absence of H4K16 acetylation.…”

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Histone Deacetylases with Antagonistic Roles inSaccharomyces cerevisiaeHeterochromatin Formation

Thurtle-Schmidt¹,

Dodson²,

Rine

2016

Genetics

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As the only catalytic member of the Sir-protein gene-silencing complex, Sir2's catalytic activity is necessary for silencing. The only known role for Sir2's catalytic activity in Saccharomyces cerevisiae silencing is to deacetylate N-terminal tails of histones H3 and H4, creating high-affinity binding sites for the Sir-protein complex, resulting in association of Sir proteins across the silenced domain. This histone deacetylation model makes the simple prediction that preemptively removing Sir2's H3 and H4 acetyl substrates, by mutating these lysines to unacetylatable arginines, or removing the acetyl transferase responsible for their acetylation, should restore silencing in the Sir2 catalytic mutant. However, this was not the case. We conducted a genetic screen to explore what aspect of Sir2's catalytic activity has not been accounted for in silencing. Mutation of a nonsirtuin histone deacetylase, Rpd3, restored Sir-protein-based silencing in the absence of Sir2's catalytic activity. Moreover, this antagonism could be mediated by either the large or the small Rpd3-containing complex. Interestingly, this restoration of silencing appeared independent of any known histone H3 or H4 substrates of Rpd3 Investigation of Sir-protein association in the Rpd3 mutant revealed that the restoration of silencing was correlated with an increased association of Sir proteins at the silencers, suggesting that Rpd3 was an antagonist of Sir2's function in nucleation of Sir proteins to the silencer. Additionally, restoration of silencing by Rpd3 was dependent on another sirtuin family member, Hst3, indicating multiple antagonistic roles for deacetylases in S. cerevisiae silencing.

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On the Mechanism of Gene Silencing in Saccharomyces cerevisiae

Cited by 14 publications

References 54 publications

Pivotal roles of PCNA loading and unloading in heterochromatin function

Pivotal roles of PCNA loading and unloading in heterochromatin function

Evolution and Functional Trajectory of Sir1 in Gene Silencing

Histone Deacetylases with Antagonistic Roles inSaccharomyces cerevisiaeHeterochromatin Formation

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