Dot1 promotes H2B ubiquitination by a methyltransferase-independent mechanism
Abstract The histone methyltransferase Dot1 is conserved from yeast to human and methylates lysine 79 of histone H3 (H3K79) on the core of the nucleosome. H3K79 methylation by Dot1 affects gene expression and the response to DNA damage, and is enhanced by monoubiquitination of the C-terminus of hist...
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| Published in | Nucleic acids research Vol. 46; no. 21; pp. 11251 - 11261 |
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| Main Authors | , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Oxford University Press
30.11.2018
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0305-1048 1362-4962 1362-4962 |
| DOI | 10.1093/nar/gky801 |
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| Abstract | Abstract
The histone methyltransferase Dot1 is conserved from yeast to human and methylates lysine 79 of histone H3 (H3K79) on the core of the nucleosome. H3K79 methylation by Dot1 affects gene expression and the response to DNA damage, and is enhanced by monoubiquitination of the C-terminus of histone H2B (H2Bub1). To gain more insight into the functions of Dot1, we generated genetic interaction maps of increased-dosage alleles of DOT1. We identified a functional relationship between increased Dot1 dosage and loss of the DUB module of the SAGA co-activator complex, which deubiquitinates H2Bub1 and thereby negatively regulates H3K79 methylation. Increased Dot1 dosage was found to promote H2Bub1 in a dose-dependent manner and this was exacerbated by the loss of SAGA-DUB activity, which also caused a negative genetic interaction. The stimulatory effect on H2B ubiquitination was mediated by the N-terminus of Dot1, independent of methyltransferase activity. Our findings show that Dot1 and H2Bub1 are subject to bi-directional crosstalk and that Dot1 possesses chromatin regulatory functions that are independent of its methyltransferase activity. |
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| AbstractList | Abstract
The histone methyltransferase Dot1 is conserved from yeast to human and methylates lysine 79 of histone H3 (H3K79) on the core of the nucleosome. H3K79 methylation by Dot1 affects gene expression and the response to DNA damage, and is enhanced by monoubiquitination of the C-terminus of histone H2B (H2Bub1). To gain more insight into the functions of Dot1, we generated genetic interaction maps of increased-dosage alleles of DOT1. We identified a functional relationship between increased Dot1 dosage and loss of the DUB module of the SAGA co-activator complex, which deubiquitinates H2Bub1 and thereby negatively regulates H3K79 methylation. Increased Dot1 dosage was found to promote H2Bub1 in a dose-dependent manner and this was exacerbated by the loss of SAGA-DUB activity, which also caused a negative genetic interaction. The stimulatory effect on H2B ubiquitination was mediated by the N-terminus of Dot1, independent of methyltransferase activity. Our findings show that Dot1 and H2Bub1 are subject to bi-directional crosstalk and that Dot1 possesses chromatin regulatory functions that are independent of its methyltransferase activity. The histone methyltransferase Dot1 is conserved from yeast to human and methylates lysine 79 of histone H3 (H3K79) on the core of the nucleosome. H3K79 methylation by Dot1 affects gene expression and the response to DNA damage, and is enhanced by monoubiquitination of the C-terminus of histone H2B (H2Bub1). To gain more insight into the functions of Dot1, we generated genetic interaction maps of increased-dosage alleles of DOT1 . We identified a functional relationship between increased Dot1 dosage and loss of the DUB module of the SAGA co-activator complex, which deubiquitinates H2Bub1 and thereby negatively regulates H3K79 methylation. Increased Dot1 dosage was found to promote H2Bub1 in a dose-dependent manner and this was exacerbated by the loss of SAGA-DUB activity, which also caused a negative genetic interaction. The stimulatory effect on H2B ubiquitination was mediated by the N-terminus of Dot1, independent of methyltransferase activity. Our findings show that Dot1 and H2Bub1 are subject to bi-directional crosstalk and that Dot1 possesses chromatin regulatory functions that are independent of its methyltransferase activity. The histone methyltransferase Dot1 is conserved from yeast to human and methylates lysine 79 of histone H3 (H3K79) on the core of the nucleosome. H3K79 methylation by Dot1 affects gene expression and the response to DNA damage, and is enhanced by monoubiquitination of the C-terminus of histone H2B (H2Bub1). To gain more insight into the functions of Dot1, we generated genetic interaction maps of increased-dosage alleles of DOT1. We identified a functional relationship between increased Dot1 dosage and loss of the DUB module of the SAGA co-activator complex, which deubiquitinates H2Bub1 and thereby negatively regulates H3K79 methylation. Increased Dot1 dosage was found to promote H2Bub1 in a dose-dependent manner and this was exacerbated by the loss of SAGA-DUB activity, which also caused a negative genetic interaction. The stimulatory effect on H2B ubiquitination was mediated by the N-terminus of Dot1, independent of methyltransferase activity. Our findings show that Dot1 and H2Bub1 are subject to bi-directional crosstalk and that Dot1 possesses chromatin regulatory functions that are independent of its methyltransferase activity.The histone methyltransferase Dot1 is conserved from yeast to human and methylates lysine 79 of histone H3 (H3K79) on the core of the nucleosome. H3K79 methylation by Dot1 affects gene expression and the response to DNA damage, and is enhanced by monoubiquitination of the C-terminus of histone H2B (H2Bub1). To gain more insight into the functions of Dot1, we generated genetic interaction maps of increased-dosage alleles of DOT1. We identified a functional relationship between increased Dot1 dosage and loss of the DUB module of the SAGA co-activator complex, which deubiquitinates H2Bub1 and thereby negatively regulates H3K79 methylation. Increased Dot1 dosage was found to promote H2Bub1 in a dose-dependent manner and this was exacerbated by the loss of SAGA-DUB activity, which also caused a negative genetic interaction. The stimulatory effect on H2B ubiquitination was mediated by the N-terminus of Dot1, independent of methyltransferase activity. Our findings show that Dot1 and H2Bub1 are subject to bi-directional crosstalk and that Dot1 possesses chromatin regulatory functions that are independent of its methyltransferase activity. The histone methyltransferase Dot1 is conserved from yeast to human and methylates lysine 79 of histone H3 (H3K79) on the core of the nucleosome. H3K79 methylation by Dot1 affects gene expression and the response to DNA damage, and is enhanced by monoubiquitination of the C-terminus of histone H2B (H2Bub1). To gain more insight into the functions of Dot1, we generated genetic interaction maps of increased-dosage alleles of DOT1. We identified a functional relationship between increased Dot1 dosage and loss of the DUB module of the SAGA co-activator complex, which deubiquitinates H2Bub1 and thereby negatively regulates H3K79 methylation. Increased Dot1 dosage was found to promote H2Bub1 in a dose-dependent manner and this was exacerbated by the loss of SAGA-DUB activity, which also caused a negative genetic interaction. The stimulatory effect on H2B ubiquitination was mediated by the N-terminus of Dot1, independent of methyltransferase activity. Our findings show that Dot1 and H2Bub1 are subject to bi-directional crosstalk and that Dot1 possesses chromatin regulatory functions that are independent of its methyltransferase activity. |
| Author | Holstege, Frank C P Stulemeijer, Iris J E Ekkebus, Reggy Sun, Su Ming El Oualid, Farid van Welsem, Tibor Srivas, Rohith Morais, Dominique Lenstra, Tineke L Vlaming, Hanneke van Leeuwen, Fred van Harten, Kirsten Poramba-Liyanage, Deepani W Ideker, Trey van Attikum, Haico Molenaar, Thom M Korthout, Tessy Ovaa, Huib |
| AuthorAffiliation | 4 Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands 2 Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands 1 Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands 5 Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA 6 UbiQ Bio B.V., 1098 XH Amsterdam, The Netherlands 3 Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands |
| AuthorAffiliation_xml | – name: 2 Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands – name: 6 UbiQ Bio B.V., 1098 XH Amsterdam, The Netherlands – name: 3 Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands – name: 5 Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA – name: 4 Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands – name: 1 Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands |
| Author_xml | – sequence: 1 givenname: Tibor surname: van Welsem fullname: van Welsem, Tibor organization: Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands – sequence: 2 givenname: Tessy orcidid: 0000-0002-7384-5923 surname: Korthout fullname: Korthout, Tessy organization: Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands – sequence: 3 givenname: Reggy surname: Ekkebus fullname: Ekkebus, Reggy organization: Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands – sequence: 4 givenname: Dominique surname: Morais fullname: Morais, Dominique organization: Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands – sequence: 5 givenname: Thom M surname: Molenaar fullname: Molenaar, Thom M organization: Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands – sequence: 6 givenname: Kirsten surname: van Harten fullname: van Harten, Kirsten organization: Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands – sequence: 7 givenname: Deepani W surname: Poramba-Liyanage fullname: Poramba-Liyanage, Deepani W organization: Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands – sequence: 8 givenname: Su Ming surname: Sun fullname: Sun, Su Ming organization: Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands – sequence: 9 givenname: Tineke L surname: Lenstra fullname: Lenstra, Tineke L organization: Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands – sequence: 10 givenname: Rohith surname: Srivas fullname: Srivas, Rohith organization: Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA – sequence: 11 givenname: Trey surname: Ideker fullname: Ideker, Trey organization: Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA – sequence: 12 givenname: Frank C P surname: Holstege fullname: Holstege, Frank C P organization: Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands – sequence: 13 givenname: Haico orcidid: 0000-0001-8590-0240 surname: van Attikum fullname: van Attikum, Haico organization: Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands – sequence: 14 givenname: Farid surname: El Oualid fullname: El Oualid, Farid organization: UbiQ Bio B.V., 1098 XH Amsterdam, The Netherlands – sequence: 15 givenname: Huib orcidid: 0000-0002-0068-054X surname: Ovaa fullname: Ovaa, Huib organization: Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands – sequence: 16 givenname: Iris J E surname: Stulemeijer fullname: Stulemeijer, Iris J E organization: Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands – sequence: 17 givenname: Hanneke orcidid: 0000-0003-1743-6428 surname: Vlaming fullname: Vlaming, Hanneke organization: Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands – sequence: 18 givenname: Fred orcidid: 0000-0002-7267-7251 surname: van Leeuwen fullname: van Leeuwen, Fred email: fred.v.leeuwen@nki.nl organization: Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30203048$$D View this record in MEDLINE/PubMed |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors wish it to be known that, in their opinion, the first two authors should be regarded as Joint First Authors. Frank Holstege, Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands. Huib Ovaa, Leiden Institute for Chemical Immunology, Leiden University Medical Center, 2333ZC Leiden, The Netherlands and Oncode Institute. Present addresses: Tineke Lenstra, Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. Hanneke Vlaming, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. |
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The histone methyltransferase Dot1 is conserved from yeast to human and methylates lysine 79 of histone H3 (H3K79) on the core of the nucleosome.... The histone methyltransferase Dot1 is conserved from yeast to human and methylates lysine 79 of histone H3 (H3K79) on the core of the nucleosome. H3K79... |
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| SubjectTerms | Chromatin - genetics Chromatin - metabolism Gene regulation, Chromatin and Epigenetics Histone-Lysine N-Methyltransferase - genetics Histone-Lysine N-Methyltransferase - metabolism Histones - metabolism Nuclear Proteins - genetics Nuclear Proteins - metabolism Protein Binding Protein Interaction Maps - genetics Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae - metabolism Saccharomyces cerevisiae Proteins - genetics Saccharomyces cerevisiae Proteins - metabolism Ubiquitination |
| Title | Dot1 promotes H2B ubiquitination by a methyltransferase-independent mechanism |
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