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The diverse functions of Dot1 and H3K79 methylation.

ABSTRACT: DOT1 (disruptor of telomeric silencing; also called Kmt4) was initially discovered in budding yeast in a genetic screen for genes whose deletion confers defects in telomeric silencing. Since the discovery ?10 years ago that Dot1 and its mammalian homolog, DOT1L (DOT1-Like), possess histone methyltransferase activity toward histone H3 Lys 79, great progress has been made in characterizing their enzymatic activities and the role of Dot1/DOT1L-mediated H3K79 methylation in transcriptional regulation, cell cycle regulation, and the DNA damage response. In addition, gene disruption in mice has revealed that mouse DOT1L plays an essential role in embryonic development, hematopoiesis, cardiac function, and the development of leukemia. The involvement of DOT1L enzymatic activity in leukemogenesis driven by a subset of MLL (mixed-lineage leukemia) fusion proteins raises the possibility of targeting DOT1L for therapeutic intervention.

SUBMITTER: Nguyen AT

PROVIDER: S-EPMC3134078 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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The diverse functions of Dot1 and H3K79 methylation.

Nguyen Anh Tram AT Zhang Yi Y

Genes & development 20110701 13

DOT1 (disruptor of telomeric silencing; also called Kmt4) was initially discovered in budding yeast in a genetic screen for genes whose deletion confers defects in telomeric silencing. Since the discovery ∼10 years ago that Dot1 and its mammalian homolog, DOT1L (DOT1-Like), possess histone methyltransferase activity toward histone H3 Lys 79, great progress has been made in characterizing their enzymatic activities and the role of Dot1/DOT1L-mediated H3K79 methylation in transcriptional regulatio ...[more]

PMID: 21724828

Similar Datasets

Dot1 and histone H3K79 methylation in natural telomeric and HM silencing.

Project description:The expression of genes residing near telomeres is attenuated through telomere position-effect variegation (TPEV). By using a URA3 reporter located at TEL-VII-L of Saccharomyces cerevisiae, it was proposed that the disruptor of telomeric silencing-1 (Dot1) regulates TPEV by catalyzing H3K79 methylation. URA3 reporter assays also indicated that H3K79 methylation is required for HM silencing. Surprisingly, a genome-wide expression analysis of H3K79 methylation-defective mutants identified only a few telomeric genes, such as COS12 at TEL-VII-L, to be subject to H3K79 methylation-dependent natural silencing. Consistently, loss of Dot1 did not globally alter Sir2 or Sir3 occupancy in subtelomeric regions, but only led to some telomere-specific changes. Furthermore, H3K79 methylation by Dot1 did not play a role in the maintenance of natural HML silencing. Therefore, commonly used URA3 reporter assays may not report on natural PEV, and therefore, studies concerning the epigenetic mechanism of silencing in yeast should also employ assays reporting on natural gene expression patterns.

| S-EPMC3085244 | biostudies-literature

Direct screening for chromatin status on DNA barcodes in yeast delineates the regulome of H3K79 methylation by Dot1.

Project description:Given the frequent misregulation of chromatin in cancer, it is important to understand the cellular mechanisms that regulate chromatin structure. However, systematic screening for epigenetic regulators is challenging and often relies on laborious assays or indirect reporter read-outs. Here we describe a strategy, Epi-ID, to directly assess chromatin status in thousands of mutants. In Epi-ID, chromatin status on DNA barcodes is interrogated by chromatin immunoprecipitation followed by deep sequencing, allowing for quantitative comparison of many mutants in parallel. Screening of a barcoded yeast knock-out collection for regulators of histone H3K79 methylation by Dot1 identified all known regulators as well as novel players and processes. These include histone deposition, homologous recombination, and adenosine kinase, which influences the methionine cycle. Gcn5, the acetyltransferase within the SAGA complex, was found to regulate histone methylation and H2B ubiquitination. The concept of Epi-ID is widely applicable and can be readily applied to other chromatin features.

| S-EPMC5179194 | biostudies-literature

Progressive methylation of ageing histones by Dot1 functions as a timer.

Project description:Post-translational modifications of histone proteins have a crucial role in regulating gene expression. If efficiently re-established after chromosome duplication, histone modifications could help propagate gene expression patterns in dividing cells by epigenetic mechanisms. We used an integrated approach to investigate the dynamics of the conserved methylation of histone H3 Lys 79 (H3K79) by Dot1. Our results show that methylation of H3K79 progressively changes after histone deposition, which is incompatible with a rapid copy mechanism. Instead, methylation accumulates on ageing histones, providing the cell with a timer mechanism to directly couple cell-cycle length to changes in chromatin modification on the nucleosome core.

| S-EPMC3166457 | biostudies-literature

Regulation of the Dot1 histone H3K79 methyltransferase by histone H4K16 acetylation.

Project description:Dot1 (disruptor of telomeric silencing-1), the histone H3 lysine 79 (H3K79) methyltransferase, is conserved throughout evolution, and its deregulation is found in human leukemias. Here, we provide evidence that acetylation of histone H4 allosterically stimulates yeast Dot1 in a manner distinct from but coordinating with histone H2B ubiquitination (H2BUb). We further demonstrate that this stimulatory effect is specific to acetylation of lysine 16 (H4K16ac), a modification central to chromatin structure. We provide a mechanism of this histone cross-talk and show that H4K16ac and H2BUb play crucial roles in H3K79 di- and trimethylation in vitro and in vivo. These data reveal mechanisms that control H3K79 methylation and demonstrate how H4K16ac, H3K79me, and H2BUb function together to regulate gene transcription and gene silencing to ensure optimal maintenance and propagation of an epigenetic state.

| S-EPMC8279004 | biostudies-literature

Dot1-dependent histone H3K79 methylation promotes activation of the Mek1 meiotic checkpoint effector kinase by regulating the Hop1 adaptor.

Project description:During meiosis, accurate chromosome segregation relies on the proper interaction between homologous chromosomes, including synapsis and recombination. The meiotic recombination checkpoint is a quality control mechanism that monitors those crucial events. In response to defects in synapsis and/or recombination, this checkpoint blocks or delays progression of meiosis, preventing the formation of aberrant gametes. Meiotic recombination occurs in the context of chromatin and histone modifications, which play crucial roles in the maintenance of genomic integrity. Here, we unveil the role of Dot1-dependent histone H3 methylation at lysine 79 (H3K79me) in this meiotic surveillance mechanism. We demonstrate that the meiotic checkpoint function of Dot1 relies on H3K79me because, like the dot1 deletion, H3-K79A or H3-K79R mutations suppress the checkpoint-imposed meiotic delay of a synapsis-defective zip1 mutant. Moreover, by genetically manipulating Dot1 catalytic activity, we find that the status of H3K79me modulates the meiotic checkpoint response. We also define the phosphorylation events involving activation of the meiotic checkpoint effector Mek1 kinase. Dot1 is required for Mek1 autophosphorylation, but not for its Mec1/Tel1-dependent phosphorylation. Dot1-dependent H3K79me also promotes Hop1 activation and its proper distribution along zip1 meiotic chromosomes, at least in part, by regulating Pch2 localization. Furthermore, HOP1 overexpression bypasses the Dot1 requirement for checkpoint activation. We propose that chromatin remodeling resulting from unrepaired meiotic DSBs and/or faulty interhomolog interactions allows Dot1-mediated H3K79-me to exclude Pch2 from the chromosomes, thus driving localization of Hop1 along chromosome axes and enabling Mek1 full activation to trigger downstream responses, such as meiotic arrest.

| S-EPMC3561090 | biostudies-literature

Dot1-dependent histone H3K79 methylation promotes the formation of meiotic double-strand breaks in the absence of histone H3K4 methylation in budding yeast.

Project description:Epigenetic marks such as histone modifications play roles in various chromosome dynamics in mitosis and meiosis. Methylation of histones H3 at positions K4 and K79 is involved in the initiation of recombination and the recombination checkpoint, respectively, during meiosis in the budding yeast. Set1 promotes H3K4 methylation while Dot1 promotes H3K79 methylation. In this study, we carried out detailed analyses of meiosis in mutants of the SET1 and DOT1 genes as well as methylation-defective mutants of histone H3. We confirmed the role of Set1-dependent H3K4 methylation in the formation of double-strand breaks (DSBs) in meiosis for the initiation of meiotic recombination, and we showed the involvement of Dot1 (H3K79 methylation) in DSB formation in the absence of Set1-dependent H3K4 methylation. In addition, we showed that the histone H3K4 methylation-defective mutants are defective in SC elongation, although they seem to have moderate reduction of DSBs. This suggests that high levels of DSBs mediated by histone H3K4 methylation promote SC elongation.

| S-EPMC4010517 | biostudies-literature

Deficiency of H3K79 histone methyltransferase Dot1-like protein (DOT1L) inhibits cell proliferation.

Project description:Dot1-like protein (DOT1L) is an evolutionarily conserved histone methyltransferase that methylates lysine 79 of histone H3 (H3K79). Mammalian DOT1L participates in the regulation of transcription, development, erythropoiesis, differentiation, and proliferation of normal cells. However, the role of DOT1L in cancer cell proliferation has not been fully elucidated. DOT1L siRNA-transfected A549 or NCI-H1299 lung cancer cells displayed a nonproliferating multinucleated phenotype. DOT1L-deficient cells also showed abnormal mitotic spindle formation and centrosome number, suggesting that DOT1L deficiency leads to chromosomal missegregation. This chromosomal instability in DOT1L-deficient cells led to cell cycle arrest at the G(1) phase and induced senescence as determined by enhanced activity of senescence-associated β-galactosidase activity. Meanwhile, overexpression of a catalytically active DOT1L, not an inactive mutant, restored DOT1L siRNA-induced phenotypes. Overall, these data imply that down-regulation of DOT1L-mediated H3K79 methylation disturbs proliferation of human cells. In addition, although H3K79 methylation is down-regulated in aged tissues, it is up-regulated in lung cancer cell lines and tumor tissues of lung cancer patients. Therefore, H3K79 methylation is a critical histone modification that regulates cell proliferation and would be a novel histone mark for aging and cancer.

| S-EPMC3285333 | biostudies-literature

Dot1 and Histone H3K79 Methylation in Natural Heterochromatic and HML/HMR Silencing

2011-02-12 | GSE27234 | GEO

Dot1 and Histone H3K79 Methylation in Natural Heterochromatic and HML-HMR Silencing

Project description:ChIP-on-Chip of Sir proteins in WT and dot1 deletion strains

2011-02-09 | E-MEXP-3108 | biostudies-arrayexpress

Dot1 and Histone H3K79 Methylation in Natural Heterochromatic and HML/HMR Silencing

Project description:Dot1 is a methyl transferase that has been shown through a reporter gene to be involved in position effect variegation of gene expression in heterochrmatic regions such as telomeres and the mating type loci in yeast. This study examines the effect of mutation of DOT1 and two other proteins involved in H3K79 methylation, SWI4 and ARD1, on gene expression relative to wt cells. Wt, and mutants of Dot1, Swi4, or Ard1 were grown, in duplicate, in liquid media to midlog phase for extraction of RNA and comparison of gene expression on Affymetrix arrays.

2011-02-12 | E-GEOD-27234 | biostudies-arrayexpress

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