TheSchizosaccharomyces pombe hst4+Gene Is aSIR2Homologue with Silencing and Centromeric Functions

Freeman-Cook, Lisa L.; Sherman, Joyce M.; Brachmann, Carrie Baker; Allshire, Robin C.; Boeke, Jef D.; Pillus, Lorraine

doi:10.1091/mbc.10.10.3171

Cited by 65 publications

(66 citation statements)

References 86 publications

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“…3B). This is consistent with the fact that expression of the S. pombe hst4 ϩ gene suppresses the strong thermosensitive and telomeric silencing phenotypes of S. cerevisiae hst3hst4 mutants, which are known to result from hyperacetylation of H3 Lys-56 (16,17,32). This suggests that Hst4 promotes deacetylation of H3 Lys-56 in S. pombe.…”

Section: Discussionsupporting

confidence: 85%

Regulation of Histone H3 Lysine 56 Acetylation in Schizosaccharomyces pombe

Xhemalçe

Miller

Driscoll

et al. 2007

Journal of Biological Chemistry

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In Saccharomyces cerevisiae, acetylation of lysine 56 (Lys-56) in the globular domain of histone H3 plays an important role in response to genotoxic agents that interfere with DNA replication. However, the regulation and biological function of this modification are poorly defined in other eukaryotes. Here we show that Lys-56 acetylation in Schizosaccharomyces pombe occurs transiently during passage through S-phase and is normally removed in G 2 . Genotoxic agents that cause DNA double strand breaks during replication elicit a delay in deacetylation of histone H3 Lys-56. In addition, mutant cells that cannot acetylate Lys-56 are acutely sensitive to genotoxic agents that block DNA replication. Moreover, we show that Spbc342.06cp, a previously uncharacterized open reading frame, encodes the functional homolog of S. cerevisiae Rtt109, and that this protein acetylates H3 Lys-56 both in vitro and in vivo. Altogether, our results indicate that both the regulation of histone H3 Lys-56 acetylation by its histone acetyltransferase and histone deacetylase and its role in the DNA damage response are conserved among two distantly related yeast model organisms.Histone acetylation corresponds to the covalent attachment of an acetyl group to a lysine residue. This modification is mediated by histone acetyltransferases (HATs) 7 and is reversible as the acetyl group can be removed through the action of histone deacetylases (HDACs). Lysine acetylation on histones is best characterized for its role in transcriptional regulation, but evidence for a crucial function during replication and DNA damage tolerance is accumulating (1-3). Indeed, newly synthesized histones that are deposited throughout the genome during replication are transiently acetylated at several lysine residues (4, 5). These include sites of acetylation in the N-terminal tails of both histones H3 and H4 (6 -8). Recently, two novel sites of acetylation in the globular domains of newly synthesized histone molecules were uncovered by mass spectrometry of Saccharomyces cerevisiae histones, lysine 91 (Lys-91) of histone H4 (9) and lysine 56 (Lys-56) of histone H3 (10 -15).H3 Lys-56 acetylation (H3 Lys-56-Ac) shows a particular link between DNA replication and DNA damage tolerance. In budding yeast, this modification occurs concomitantly with DNA replication as virtually all the newly synthesized histone H3 molecules deposited throughout the genome are Lys-56-acetylated, whereas in the G 2 /M-phase of the cell cycle the vast majority of H3 Lys-56 is deacetylated (11,(15)(16)(17). However, in response to DNA breaks during replication, histone H3 Lys-56 acetylation is maintained in a DNA damage checkpointdependent manner. In S. cerevisiae this modification plays a key role in surviving DNA damage as cells in which histone H3 cannot be acetylated at Lys-56 are acutely sensitive to genotoxic agents that interfere with DNA replication (10 -13).The deacetylation of H3 Lys-56 requires the Sir2-related HDACs Hst3 and Hst4 (16,17). Hst3 and Hst4 are cell cycles regulated with peak...

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Section: Discussionsupporting

confidence: 85%

Regulation of Histone H3 Lysine 56 Acetylation in Schizosaccharomyces pombe

Xhemalçe

Miller

Driscoll

et al. 2007

Journal of Biological Chemistry

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“…Perhaps these proteins are deacetylated by SIR2-like proteins to modulate their biological activities. Indeed, mutation of a fission yeast SIR2 homolog results in sensitivity to microtubuledepolymerizing drugs and chromosome loss (26). Likewise, in the fungus Candida albicans, mutation of a SIR2 homolog leads to genomic instability, which is correlated with clinical pathology (27).…”

Section: Discussionmentioning

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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881

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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“…This relocalization requires the function of DNA damage checkpoint proteins and results in decreased telomeric silencing (Martin et al, 1999;McAnish et al, 1999;Mills et al, 1999). The Sir2-related Hst3 and Hst4 proteins of S. cerevisiae and Hst4 of Schizosaccharomyces pombe also contribute to radiation resistance (Brachmann et al, 1995;Freeman-Cook et al, 1999). In consonance with all these observations, the dot1 mutant, which shows reduced telomeric silencing and altered telomere length (Singer et al, 1998), also displays defects in the localization of Sir proteins and in the meiotic checkpoint that responds to unrepaired DSBs.…”

Section: Considerations About Heterochromatin Checkpoints and Dna Dmentioning

confidence: 99%

Role for the Silencing Protein Dot1 in Meiotic Checkpoint Control

San-Segundo

Roeder

2000

MBoC

161

163

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During the meiotic cell cycle, a surveillance mechanism called the "pachytene checkpoint" ensures proper chromosome segregation by preventing meiotic progression when recombination and chromosome synapsis are defective. The silencing protein Dot1 (also known as Pch1) is required for checkpoint-mediated pachytene arrest of the zip1 and dmc1 mutants of Saccharomyces cerevisiae. In the absence of DOT1, the zip1 and dmc1 mutants inappropriately progress through meiosis, generating inviable meiotic products. Other components of the pachytene checkpoint include the nucleolar protein Pch2 and the heterochromatin component Sir2. In dot1, disruption of the checkpoint correlates with the loss of concentration of Pch2 and Sir2 in the nucleolus. In addition to its checkpoint function, Dot1 blocks the repair of meiotic double-strand breaks by a Rad54-dependent pathway of recombination between sister chromatids. In vegetative cells, mutation of DOT1 results in delocalization of Sir3 from telomeres, accounting for the impaired telomeric silencing in dot1.

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TheSchizosaccharomyces pombe hst4⁺Gene Is aSIR2Homologue with Silencing and Centromeric Functions

Cited by 65 publications

References 86 publications

Regulation of Histone H3 Lysine 56 Acetylation in Schizosaccharomyces pombe

Regulation of Histone H3 Lysine 56 Acetylation in Schizosaccharomyces pombe

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

Role for the Silencing Protein Dot1 in Meiotic Checkpoint Control

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