MLL1 is regulated by KSHV LANA and is important for virus latency

Min Tan, Shijun Li, Franceline Juillard, Rute Chitas, Tânia F. Custódio, Han Xue, Agnieszka Szymula, Qiming Sun, Bing Liu, Ángel L. Álvarez, She Chen, Jing Huang, J. Pedro Simas, Colin E. McVey, Kenneth M. Kaye

Resultado de pesquisarevisão de pares

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Resumo

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.
Idioma originalEnglish
Páginas (de-até)12895-12911
Número de páginas17
RevistaNucleic Acids Research
Volume49
Número de emissão22
DOIs
Estado da publicaçãoPublicado - 16 dez 2021

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