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Structural basis for activation of Dot1L methyltransferase on the nucleosome by histone H2BK120 ubiquitylation

Cathy J. Anderson, Matthew R. Baird, Allen Hsu, Emily H. Barbour, Yuka Koyama, Mario J. Borgnia, Robert K. McGinty
doi: https://doi.org/10.1101/503128
Cathy J. Anderson
1Department of Biochemistry and Biophysics, School of Medicine, The University of North Carolina, Chapel Hill, NC 27599, USA
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Matthew R. Baird
2Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina, Chapel Hill, NC 27599, USA
4Present address: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
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Allen Hsu
3Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709
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Emily H. Barbour
2Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina, Chapel Hill, NC 27599, USA
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Yuka Koyama
2Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina, Chapel Hill, NC 27599, USA
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Mario J. Borgnia
3Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709
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Robert K. McGinty
2Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina, Chapel Hill, NC 27599, USA
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  • For correspondence: rmcginty@email.unc.edu
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Summary

Histone H3 lysine 79 (H3K79) methylation is enriched on actively transcribed genes, and its misregulation is a hallmark of leukemia. Methylation of H3K79, which resides on the structured disk face of the nucleosome, is mediated by the Dot1L methyltransferase. Dot1L activity is part of a trans-histone crosstalk pathway, requiring prior histone H2B ubiquitylation of lysine 120 (H2BK120ub) for optimal activity. However, the molecular details describing both how Dot1L binds to the nucleosome and why Dot1L is activated by H2BK120 ubiquitylation are unknown. Here we present the cryo-EM structure of Dot1L bound to a nucleosome reconstituted with a site-specifically ubiquitylated H2BK120. The structure reveals that Dot1L engages the nucleosome acidic patch using an arginine anchor and occupies a conformation poised for methylation. Ubiquitin directly interacts with Dot1L and is positioned as a clamp on the nucleosome interacting region of Dot1L. Using our structure, we identify point mutations that disrupt the nucleosome-specific and ubiquitin-dependent activities of Dot1L. This study establishes a path to better understand Dot1L function in normal and leukemia cells.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 20, 2018.
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Structural basis for activation of Dot1L methyltransferase on the nucleosome by histone H2BK120 ubiquitylation
Cathy J. Anderson, Matthew R. Baird, Allen Hsu, Emily H. Barbour, Yuka Koyama, Mario J. Borgnia, Robert K. McGinty
bioRxiv 503128; doi: https://doi.org/10.1101/503128
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Structural basis for activation of Dot1L methyltransferase on the nucleosome by histone H2BK120 ubiquitylation
Cathy J. Anderson, Matthew R. Baird, Allen Hsu, Emily H. Barbour, Yuka Koyama, Mario J. Borgnia, Robert K. McGinty
bioRxiv 503128; doi: https://doi.org/10.1101/503128

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