Site-specific Phosphorylation of Histone H3K36 Methyltransferase Set2p and Demethylase Jhd1p is Required for Stress Responses in Saccharomyces cerevisiae

Separovich, Ryan J.; Wong, Mandy W M; Bartolec, Tara K.; Hamey, Joshua J.; Wilkins, Marc R.

doi:10.1016/j.jmb.2022.167500

Cited by 4 publications

(8 citation statements)

References 110 publications

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“…Set2 interacts with the histone chaperone Spt6 and the Iws1/Spn1 component of the RNA polymerase II elongation complex and this interaction is crucial for the expression of highly transcribed mRNAs such as those encoding ribosomal proteins (Reim, 2020). Conversely, demethylases Jhd1p, Jhd2p, Rph1p, and Gis1p remove H3K36 marks (Separovich, 2022). We found strong correlations between the PT score and phosphopeptides in the BUR kinase subunit Sgv1, Bur2, Set2, Iws1/Spn1 and its binding partner Spt6, the Sin3 component of the Rpd3S complex, Rph1 as well as Gis1.…”

Section: Supplemental Textmentioning

confidence: 66%

“…Interestingly, phospho-residuals of a number of proteins involved in dephosphorylation showed the highest mean correlation with the PT score. Finally, we noticed strong correlations between the PT score and phosphorylation events on enzymes involved in histone modification centered on H3K36 trimethylation, an important prerequisite for the expression of stress response genes (McDaniel and Strahl, 2017; Separovich et al, 2022). Together, these results revealed widespread adaptation of cellular processes coincident with changes in the PT network state reaching far beyond the core energy metabolism.…”

Section: Resultsmentioning

confidence: 85%

“…Fig) . It has been reported that H3K36 trimethylation is important to prevent bidirectional (cryptic) transcription within gene bodies. In turn, the expression of nutrient-sensitive as well as stress response genes depends on the presence of the histone methylase Set2 (McDaniel, 2017;Separovich, 2022). Set2 mediates co-transcriptional histone modification, which was further shown to depend on the cyclin-dependent kinase Bur1 and the Bur2 cyclin (Hossain, 2013).…”

Section: Supplemental Textmentioning

confidence: 99%

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Large-scale changes of molecular network states explain complex traits

Weith

Großbach

Clément-Ziza

et al. 2022

Preprint

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The complexity of many cellular and organismal traits results from poorly understood mechanisms integrating genetic and environmental factors via molecular networks. Here, we show when and how genetic perturbations lead to molecular changes that are confined to small parts of a network versus when they lead to large-scale adaptations of global network states. Integrating multi-omics profiling of genetically heterogeneous budding and fission yeast strains with an array of cellular traits identified a central state transition of the yeast molecular network that is related to PKA and TOR (PT) signaling. Genetic variants affecting this PT state globally shifted the molecular network along a single-dimensional axis, thereby modulating processes including energy- and amino acid metabolism, transcription, translation, cell cycle control and cellular stress response. We propose that genetic effects can propagate through large parts of molecular networks because of the functional requirement to centrally coordinate the activity of fundamental cellular processes.

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Section: Supplemental Textmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 85%

Section: Supplemental Textmentioning

confidence: 99%

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Large-scale changes of molecular network states explain complex traits

Weith

Großbach

Clément-Ziza

et al. 2022

Preprint

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“…These sites were all identified previously in our systematic mapping of in vivo Dot1p phosphosites [38], and we did not analyse in vitro sites that we did not find, or have not been reported, on Dot1p in yeast cells (e.g., S46, S49). To investigate the collective effects of Dot1p phosphorylation, we also analysed yeast strains carrying simultaneous phosphonull ( allAla ) or phosphomimetic ( allAsp ) mutations of 14 sites on Dot1p from our phosphosite mutant library [65]. Analysis of DOT1 mutant strains by spot plate assays showed that several phosphosite mutations sensitised yeast cells to UV radiation, albeit to a smaller degree than DOT1 deletion (Fig.…”

Section: Resultsmentioning

confidence: 99%

Proline‐directed yeast and human MAP kinases phosphorylate the Dot1p/DOT1L histone H3K79 methyltransferase

Separovich,

Karakatsanis,

Gao

et al. 2024

The FEBS Journal

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Disruptor of telomeric silencing 1 (Dot1p) is an exquisitely conserved histone methyltransferase and is the sole enzyme responsible for H3K79 methylation in the budding yeast Saccharomyces cerevisiae. It has been shown to be highly phosphorylated in vivo; however, the upstream kinases that act on Dot1p are almost entirely unknown in yeast and all other eukaryotes. Here, we used in vitro and in vivo kinase discovery approaches to show that mitogen‐activated protein kinase HOG1 (Hog1p) is a bona fide kinase of the Dot1p methyltransferase. In vitro kinase assays showed that Hog1p phosphorylates Dot1p at multiple sites, including at several proline‐adjacent sites that are consistent with known Hog1p substrate preferences. The activity of Hog1p was specifically enhanced at these proline‐adjacent sites on Dot1p upon Hog1p activation by the osmostress‐responsive MAP kinase kinase PBS2 (Pbs2p). Genomic deletion of HOG1 reduced phosphorylation at specific sites on Dot1p in vivo, providing further evidence for Hog1p kinase activity on Dot1p in budding yeast cells. Phenotypic analysis of knockout and phosphosite mutant yeast strains revealed the importance of Hog1p‐catalysed phosphorylation of Dot1p for cellular responses to ultraviolet‐induced DNA damage. In mammalian systems, this kinase–substrate relationship was found to be conserved: human DOT1L (the ortholog of yeast Dot1p) can be phosphorylated by the proline‐directed kinase p38β (also known as MAPK11; the ortholog of yeast Hog1p) at multiple sites in vitro. Taken together, our findings establish Hog1p and p38β as newly identified upstream kinases of the Dot1p/DOT1L H3K79 methyltransferase enzymes in eukaryotes.

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“…34460, lot no. 172032877), as described previously ( 88 ). Lysates were also immunoblotted against PGK1 as a loading control, using an anti-3-phosphoglycerate antibody (Molecular Probes, cat.…”

Section: Methodsmentioning

confidence: 99%

Methylation of elongation factor 1A by yeast Efm4 or human eEF1A-KMT2 involves a beta-hairpin recognition motif and crosstalks with phosphorylation

Hamey,

Nguyen,

Haddad

et al. 2024

Journal of Biological Chemistry

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Site-specific Phosphorylation of Histone H3K36 Methyltransferase Set2p and Demethylase Jhd1p is Required for Stress Responses in Saccharomyces cerevisiae

Cited by 4 publications

References 110 publications

Large-scale changes of molecular network states explain complex traits

Large-scale changes of molecular network states explain complex traits

Proline‐directed yeast and human MAP kinases phosphorylate the Dot1p/DOT1L histone H3K79 methyltransferase

Methylation of elongation factor 1A by yeast Efm4 or human eEF1A-KMT2 involves a beta-hairpin recognition motif and crosstalks with phosphorylation

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