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Cited by 211Genomics and Chromatin DynamicsEpigenetics and DNA MethylationCancer-related gene regulation

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DOT1L and H3K79 Methylation in Transcription and Genomic Stability

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Wood, Katherine, Tellier, Michael, Murphy, Shona·2018·Biomolecules
DOI 10.3390/biom8010011PMC PMC5871980
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Abstract

The organization of eukaryotic genomes into chromatin provides challenges for the cell to accomplish basic cellular functions, such as transcription, DNA replication and repair of DNA damage. Accordingly, a range of proteins modify and/or read chromatin states to regulate access to chromosomal DNA. Yeast Dot1 and the mammalian homologue DOT1L are methyltransferases that can add up to three methyl groups to histone H3 lysine 79 (H3K79). H3K79 methylation is implicated in several processes, including transcription elongation by RNA polymerase II, the DNA damage response and cell cycle checkpoint activation. DOT1L is also an important drug target for treatment of mixed lineage leukemia (MLL)-rearranged leukemia where aberrant transcriptional activation is promoted by DOT1L mislocalisation. This review summarizes what is currently known about the role of Dot1/DOT1L and H3K79 methylation in transcription and genomic stability.

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Figure 1 Representative genome browser track of read coverage profiles of RNA polymerase II (RNAPII) Ser5P (initiation complex), DOT1L and different histone marks (ubiquitination of histone 2B lysine 120 (H2BK120ub), histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 36 trimethylation (H3K36me3), histone 3 lysine 79 mon-, di- and tri-methylation (H3K79me1, H3K79me2 and H3K79me3, respectively)) on two active human protein-coding genes, CDK9 and KPNB1, in the NCITT cell line (chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) data from [49,57]). Read coverage is presented on the left side of each ChIP-seq. The arrow above the gene represents the sense of transcription. All three H3K79 methylation states display a peak immediately downstream of the H3K4me3 peak but upstream of the H3K36me3 broad peak.
Figure 1 Representative genome browser track of read coverage profiles of RNA polymerase II (RNAPII) Ser5P (initiation complex), DOT1L and different histone marks (ubiquitination of histone 2B lysine 120 (H2BK120ub), histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 36 trimethylation (H3K36me3), histone 3 lysine 79 mon-, di- and tri-methylation (H3K79me1, H3K79me2 and H3K79me3, respectively)) on two active human protein-coding genes, CDK9 and KPNB1, in the NCITT cell line (chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) data from [49,57]). Read coverage is presented on the left side of each ChIP-seq. The arrow above the gene represents the sense of transcription. All three H3K79 methylation states display a peak immediately downstream of the H3K4me3 peak but upstream of the H3K36me3 broad peak.CC BY · PubMed Central
Figure 2 Function(s) of DOT1L in transcription. DOT1L is a histone H3 lysine 79 (H3K79) methylase which catalyses the mono-, di- and trimethylation of H3K79 in a non-processive manner using S-adenosylmethionine as a cofactor. No H3K79 demethylase has been identified, although there is evidence that H3K79 methylation is reversible. H3K79 methylation shows a high correlation with transcriptional activity. The requirement for H2B lysine ubiquitination for DOT1L activity and the interaction of DOT1L with RNA Pol II phosphorylated on serine 2 and/or serine 5 of its C-terminal domain (CTD) are potential mechanisms recruiting DOT1L to active genes. DOT1L is found in various eukaryotic transcription elongation complexes and its activity varies with the activity of members of these complexes and hence transcription elongation, supporting a role for DOT1L in the transcription of at least a subset of genes. H3K79 methylation likely functions in transcription via the recruitment of “readers” which act directly or indirectly to affect RNA Pol II activity.
Figure 2 Function(s) of DOT1L in transcription. DOT1L is a histone H3 lysine 79 (H3K79) methylase which catalyses the mono-, di- and trimethylation of H3K79 in a non-processive manner using S-adenosylmethionine as a cofactor. No H3K79 demethylase has been identified, although there is evidence that H3K79 methylation is reversible. H3K79 methylation shows a high correlation with transcriptional activity. The requirement for H2B lysine ubiquitination for DOT1L activity and the interaction of DOT1L with RNA Pol II phosphorylated on serine 2 and/or serine 5 of its C-terminal domain (CTD) are potential mechanisms recruiting DOT1L to active genes. DOT1L is found in various eukaryotic transcription elongation complexes and its activity varies with the activity of members of these complexes and hence transcription elongation, supporting a role for DOT1L in the transcription of at least a subset of genes. H3K79 methylation likely functions in transcription via the recruitment of “readers” which act directly or indirectly to affect RNA Pol II activity.CC BY · PubMed Central
Figure 3 The role of Dot1 in telomeric silencing. Telomeric DNA silencing in Saccharomyces cerevisiae is established by the binding of the Sir proteins, including Sir3, to chromatin. Competition between H3K79 methylation by Dot1 and Sir protein binding regulates heterochromatin formation at telomeres. Methylation of H3K79 prevents the binding of Sir3 and therefore disrupts telomeric silencing. Conversely, binding of Sir3 to unmethylated H3K79 prevents the interaction of Dot1 with chromatin by outcompeting Dot1 for binding to a basic patch on histone H4 which is essential for Dot1 recruitment and H3K79 methylation.
Figure 3 The role of Dot1 in telomeric silencing. Telomeric DNA silencing in Saccharomyces cerevisiae is established by the binding of the Sir proteins, including Sir3, to chromatin. Competition between H3K79 methylation by Dot1 and Sir protein binding regulates heterochromatin formation at telomeres. Methylation of H3K79 prevents the binding of Sir3 and therefore disrupts telomeric silencing. Conversely, binding of Sir3 to unmethylated H3K79 prevents the interaction of Dot1 with chromatin by outcompeting Dot1 for binding to a basic patch on histone H4 which is essential for Dot1 recruitment and H3K79 methylation.CC BY · PubMed Central
Figure 4 The role of Dot1 in the DNA damage response. The yeast proteins are shown, and the steps in which Dot1 has a positive effect are outlined in red. Several different DNA repair pathways can be used to respond to different types of DNA damage, and Dot1 is implicated in a number of these. Loss of H3K79me impairs ultraviolet (UV)-induced lesion repair pathways, leading to UV-hypersensitivity. Dot1 maintains genomic integrity by inhibiting the translesion synthesis (TLS) pathway in response to alkylating agents. Recruitment of Dot1 and subsequent recruitment of Rad9 are required for regulating the 5′–3′ resection step in homologous recombination (HR)-mediated repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSBs). Additionally, H3K79 methylation is required for cohesin recruitment, key for maintaining chromosome structure and for efficient sister chromatid recombination (SCR) to repair DSBs Dot1 is also required for checkpoint function at both G1 and G2. Following recognition and binding of sensor proteins to DNA damage sites, mediator proteins including Rad9 are recruited and activated by phosphorylation. H3K79 methylation by Dot1 is essential for the recruitment of Rad9 and phosphorylation of the downstream transducer protein Rad53, allowing the cell to enter an arrest phenotype at G1/S or G2 upon DNA damage.
Figure 4 The role of Dot1 in the DNA damage response. The yeast proteins are shown, and the steps in which Dot1 has a positive effect are outlined in red. Several different DNA repair pathways can be used to respond to different types of DNA damage, and Dot1 is implicated in a number of these. Loss of H3K79me impairs ultraviolet (UV)-induced lesion repair pathways, leading to UV-hypersensitivity. Dot1 maintains genomic integrity by inhibiting the translesion synthesis (TLS) pathway in response to alkylating agents. Recruitment of Dot1 and subsequent recruitment of Rad9 are required for regulating the 5′–3′ resection step in homologous recombination (HR)-mediated repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSBs). Additionally, H3K79 methylation is required for cohesin recruitment, key for maintaining chromosome structure and for efficient sister chromatid recombination (SCR) to repair DSBs Dot1 is also required for checkpoint function at both G1 and G2. Following recognition and binding of sensor proteins to DNA damage sites, mediator proteins including Rad9 are recruited and activated by phosphorylation. H3K79 methylation by Dot1 is essential for the recruitment of Rad9 and phosphorylation of the downstream transducer protein Rad53, allowing the cell to enter an arrest phenotype at G1/S or G2 upon DNA damage.CC BY · PubMed Central
Figure 5 The role of DOT1L in leukemogenesis. The C-terminus of MLL is an H3K4 methyltransferase. Constitutive activation of a leukemic transcriptional program, including the HoxA9 gene, occurs through mislocalisation of DOT1L and its associated proteins through the interaction of DOT1L with fusion partners of the MLL N-terminus. DOT1L-mediated H3K79 hypermethylation and inhibition of the SIRT1-SUV39H1 complex, which normally represses MLL fusion target genes, promote the constitutive activation of the target genes resulting in leukemic transformation. Small molecules can inhibit DOT1L methyltransferase activity blocking de novo H3K79 methylation and leukemogenic gene expression.
Figure 5 The role of DOT1L in leukemogenesis. The C-terminus of MLL is an H3K4 methyltransferase. Constitutive activation of a leukemic transcriptional program, including the HoxA9 gene, occurs through mislocalisation of DOT1L and its associated proteins through the interaction of DOT1L with fusion partners of the MLL N-terminus. DOT1L-mediated H3K79 hypermethylation and inhibition of the SIRT1-SUV39H1 complex, which normally represses MLL fusion target genes, promote the constitutive activation of the target genes resulting in leukemic transformation. Small molecules can inhibit DOT1L methyltransferase activity blocking de novo H3K79 methylation and leukemogenic gene expression.CC BY · PubMed Central

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Metadata

Authors
Wood, K., Tellier, M., & Murphy, S.
Affiliations
  • University of Manchester (GB)
  • University of Oxford (GB)
Corresponding author
  • Tellier, Michael
  • Murphy, Shona
ORCID
Venue
Biomolecules
Publisher
MDPI AG
Published
2018-02-27
Volume
8
Issue
1
Pages
11
ISSN
2218-273X (ISSN-L)
DOI
10.3390/biom8010011
PMC
PMC5871980
OpenAlex
W2791712220
Cited by
209
References
110
Citations by year
2026: 18 · 2025: 23 · 2024: 23 · 2023: 18 · 2022: 34 · 2021: 33 · 2020: 27 · 2019: 28 · 2018: 5
FWCI
2.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomolecules (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Wellcome Trust (WT106134AIA)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
Keywords
DOT1L, H3K79 methylation, histone methyltransferase, chromatin organization, transcription elongation, RNA polymerase II, DNA damage response, cell cycle checkpoints, genome stability, MLL-rearranged leukemia, histone modifications
MeSH terms
Animals, Histones, Humans, Histone-Lysine N-Methyltransferase, Yeasts, Histone Code, Genomic Instability, Transcription Elongation, Genetic

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