Abstract
Mixed lineage leukemia 1 (MLL1) is a histone methyltransferase. Kaposi's sarcoma-associated herpesvirus (KSHV) is a leading cause of malignancy in AIDS. KSHV latently infects tumor cells and its genome is decorated with epigenetic marks. Here, we show that KSHV latency-associated nuclear antigen (LANA) recruits MLL1 to viral DNA where it establishes H3K4me3 modifications at the extensive KSHV terminal repeat elements during primary infection. LANA interacts with MLL1 complex members, including WDR5, integrates into the MLL1 complex, and regulates MLL1 activity. We describe the 1.5-Å crystal structure of N-terminal LANA peptide complexed with MLL1 complex member WDR5, which reveals a potential regulatory mechanism. Disruption of MLL1 expression rendered KSHV latency establishment highly deficient. This deficiency was rescued by MLL1 but not by catalytically inactive MLL1. Therefore, MLL1 is LANA regulable and exerts a central role in virus infection. These results suggest broad potential for MLL1 regulation, including by non-host factors.
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, Viral / chemistry
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Antigens, Viral / genetics*
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Antigens, Viral / metabolism
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Cell Line, Tumor
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Crystallography, X-Ray
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DNA, Viral / genetics
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DNA, Viral / metabolism
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Gene Expression Regulation, Viral*
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Gene Knockdown Techniques
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Herpesvirus 8, Human / genetics*
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Herpesvirus 8, Human / metabolism
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Herpesvirus 8, Human / physiology
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Histone-Lysine N-Methyltransferase / chemistry
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Histone-Lysine N-Methyltransferase / genetics*
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Histone-Lysine N-Methyltransferase / metabolism
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Host-Pathogen Interactions / genetics
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Humans
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Intracellular Signaling Peptides and Proteins / chemistry
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Myeloid-Lymphoid Leukemia Protein / chemistry
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Myeloid-Lymphoid Leukemia Protein / genetics*
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Myeloid-Lymphoid Leukemia Protein / metabolism
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Protein Binding
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Protein Conformation
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Sarcoma, Kaposi / genetics*
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Sarcoma, Kaposi / virology
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Virus Latency / genetics*
Substances
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Antigens, Viral
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DNA, Viral
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Intracellular Signaling Peptides and Proteins
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KMT2A protein, human
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Nuclear Proteins
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WDR5 protein, human
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latency-associated nuclear antigen
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Myeloid-Lymphoid Leukemia Protein
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Histone-Lysine N-Methyltransferase