PRB1 Is Required for Clipping of the Histone H3 N Terminal Tail in Saccharomyces cerevisiae

Xue, Yong; Vashisht, Ajay A.; Tan, Yuliang; Su, Trent; Wohlschlegel, James A.

doi:10.1371/journal.pone.0090496

Cited by 24 publications

(29 citation statements)

References 43 publications

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“…Nonetheless, it remains unclear whether, when, and how Prb1 might enter the nucleus from the vacuole to access chromatin. Also, Prb1 cleaved H3 at lysine residues in vitro, but independent studies confirmed that the in vivo clipping activity is sensitive to serine protease inhibitors (46,48) and mutation of H3 to H3-S22A diminishes H3 clipping (Fig. 3A).…”

Section: Deletion Of Multiple Candidate Genes Encoding Metabolic Protmentioning

confidence: 84%

“…By contrast, yeast studies showed that Gdh1 was present in a fraction with clipping activity, but whole-cell extracts from GDH1 mutants did not affect clipping in vitro (48). Because we showed that Gdh1 had a role in regulating chromatin silencing, we asked whether it also functioned in H3 clipping in vivo through both biochemical and genetic approaches.…”

Section: Gdh1 Regulates Recruitment Of Sir Proteins To Silent Chromatmentioning

confidence: 91%

“…Recent work suggested that a vacuolar protease encoded by PRB1 has clipping activity in budding yeast during the early stationary phase (48). Nonetheless, it remains unclear whether, when, and how Prb1 might enter the nucleus from the vacuole to access chromatin.…”

Section: Deletion Of Multiple Candidate Genes Encoding Metabolic Protmentioning

confidence: 99%

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Functions for diverse metabolic activities in heterochromatin

Xue

Pillus

2016

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

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Growing evidence demonstrates that metabolism and chromatin dynamics are not separate processes but that they functionally intersect in many ways. For example, the lysine biosynthetic enzyme homocitrate synthase was recently shown to have unexpected functions in DNA damage repair, raising the question of whether other amino acid metabolic enzymes participate in chromatin regulation. Using an in silico screen combined with reporter assays, we discovered that a diverse range of metabolic enzymes function in heterochromatin regulation. Extended analysis of the glutamate dehydrogenase 1 (Gdh1) revealed that it regulates silent information regulator complex recruitment to telomeres and ribosomal DNA. Enhanced N-terminal histone H3 proteolysis is observed in GDH1 mutants, consistent with telomeric silencing defects. A conserved catalytic Asp residue is required for Gdh1's functions in telomeric silencing and H3 clipping. Genetic modulation of α-ketoglutarate levels demonstrates a key regulatory role for this metabolite in telomeric silencing. The metabolic activity of glutamate dehydrogenase thus has important and previously unsuspected roles in regulating chromatin-related processes.I n eukaryotic nuclei, DNA is wrapped around histones to form nucleosomes, the basic subunits of chromatin (1). The physical and chemical properties of chromatin are regulated by at least two types of enzymatic activities: chromatin remodeling and posttranslational modifications of histones and chromatin-associated proteins (2, 3). These enzymatic activities directly determine the accessibility of DNA for transcription, replication, and repair.In Saccharomyces cerevisiae, three genomic regions are known to contain loci repressed by chromatin-related activities. These include the HM silent mating-type loci (HMR and HML), regions within the ribosomal DNA (rDNA), and some telomeres. Transcriptional silencing at these loci is established and maintained by a number of factors, including the Sirtuin class III deacetylase activity of silent information protein 2 (Sir2). Notably, Sir2 uses NAD + as a cofactor to deacetylate histones H3 and H4 in newly deposited nucleosomes. Other than Sir2, the composition of the silencing complexes and the mechanisms of silencing are different for the three silenced regions, with the telomeres and the HM loci more similar to each other and the rDNA locus having distinct features (reviewed in ref. 4). Silencing at telomeres and the HM loci was long considered to follow a sequential model: initial deacetylation by Sir2 creates binding sites for Sir3 and Sir4, which in turn regulate the spreading of Sir2 across these regions (5). More recent high-resolution studies report a less uniform landscape for silenced chromatin (6), although the central importance of the Sir proteins remains clear. They, together with transcription factors including Rap1 and Abf1, form a multisubunit silencing complex known as the silent information regulator (SIR) complex. Silencing at the rDNA locus does not involve the SIR complex but ra...

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Section: Deletion Of Multiple Candidate Genes Encoding Metabolic Protmentioning

confidence: 84%

Section: Gdh1 Regulates Recruitment Of Sir Proteins To Silent Chromatmentioning

confidence: 91%

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Functions for diverse metabolic activities in heterochromatin

Xue

Pillus

2016

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

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“…In Saccharomyces cerevisiae , another enzyme was found to proteolytically clip the H3 tail. While purified vacuolar protease B (Prb1) cleaves yeast histone H3 between Lys23 and Ala24 in vitro, PRB1 -dependent serine endopeptidase generates a single H3 form via cleavage between Ala21 and Thr22 in vivo [28, 29]. Other enzymes have been reported to cleave H3 as well, such as foot-and-mouth disease virus (FMDV) protease 3C–with cleavage site Leu20-Ala21–, suggesting the existence of several protease classes that can clip the N-terminal of H3 [28, 30].…”

Section: Histone H3 Clipping and Its Significancementioning

confidence: 99%

“…The endopeptidase activity is regulated during the activation of different pathways leading to gene expression, and as elaborated by Xue et al . [29], Prb1 is responsible for most H3 N-terminus cleavage events in the yeast stationary phase. Although purified protein samples of Prb1 were reported to cleave histone H3 at Lys23-Ala24 exclusively in vitro, PRB1 is still required for the nuclear H3 endopeptidase activity observed in vivo [29].…”

Section: Histone H3 Clipping and Its Significancementioning

confidence: 99%

Histone Cleavage as a Mechanism for Epigenetic Regulation: Current Insights and Perspectives

Zhou¹,

Wu²,

Alam³

et al. 2014

CMM

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Discovered over a century ago, histones constitute one of the oldest families of proteins and have been remarkably conserved throughout eukaryotic evolution. However, only for the past 30 years have histones demonstrated that their influence extends far beyond packaging DNA. To create the various chromatin structures that are necessary for DNA function in higher eukaryotes, histones undergo post-translational modifications. While many such modifications are well documented, others, such as histone tail cleavage are less understood. Recent studies have discovered several proteases that cleave histones and have suggested roles for clipped histones in stem cell differentiation and aging in addition to infection and inflammation; the underlying mechanisms, however, are uncertain. One histone class in particular, histone H3, has received outstanding interest due to its numerous N-terminal modification sites and prevalence in regulating homeostatic processes. Here, with special consideration of H3, we will discuss the novel findings regarding histone proteolytic cleavage as well as their significance in the studies of immunology and epigenetics.

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Histone proteolysis: A proposal for categorization into ‘clipping’ and ‘degradation’

et al. 2014

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We propose for the first time to divide histone proteolysis into “histone degradation” and the epigenetically connoted “histone clipping”. Our initial observation is that these two different classes are very hard to distinguish both experimentally and biologically, because they can both be mediated by the same enzymes. Since the first report decades ago, proteolysis has been found in a broad spectrum of eukaryotic organisms. However, the authors often not clearly distinguish or determine whether degradation or clipping was studied. Given the importance of histone modifications in epigenetic regulation we further elaborate on the different ways in which histone proteolysis could play a role in epigenetics. Finally, unanticipated histone proteolysis has probably left a mark on many studies of histones in the past. In conclusion, we emphasize the significance of reviving the study of histone proteolysis both from a biological and an experimental perspective.

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PRB1 Is Required for Clipping of the Histone H3 N Terminal Tail in Saccharomyces cerevisiae

Cited by 24 publications

References 43 publications

Functions for diverse metabolic activities in heterochromatin

Functions for diverse metabolic activities in heterochromatin

Histone Cleavage as a Mechanism for Epigenetic Regulation: Current Insights and Perspectives

Histone proteolysis: A proposal for categorization into ‘clipping’ and ‘degradation’

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