Loss of TIP60 (KAT5) abolishes H2AZ lysine 7 acetylation and causes p53, INK4A, and ARF-independent cell cycle arrest.

Autor: Wichmann J; Walter & Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia., Pitt C; Walter & Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia., Eccles S; Walter & Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia., Garnham AL; Walter & Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia., Li-Wai-Suen CSN; Walter & Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia., May R; Walter & Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia., Allan E; Walter & Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; Cancer Therapeutics CRC, Parkville, VIC, Australia., Wilcox S; Walter & Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia., Herold MJ; Walter & Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia., Smyth GK; Walter & Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; School of Mathematics and Statistics, University of Melbourne, Parkville, VIC, Australia., Monahan BJ; Walter & Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.; Cancer Therapeutics CRC, Parkville, VIC, Australia., Thomas T; Walter & Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia. tthomas@wehi.edu.au.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia. tthomas@wehi.edu.au., Voss AK; Walter & Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia. avoss@wehi.edu.au.; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia. avoss@wehi.edu.au.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2022 Jul 20; Vol. 13 (7), pp. 627. Date of Electronic Publication: 2022 Jul 20.
DOI: 10.1038/s41419-022-05055-6
Abstrakt: Histone acetylation is essential for initiating and maintaining a permissive chromatin conformation and gene transcription. Dysregulation of histone acetylation can contribute to tumorigenesis and metastasis. Using inducible cre-recombinase and CRISPR/Cas9-mediated deletion, we investigated the roles of the histone lysine acetyltransferase TIP60 (KAT5/HTATIP) in human cells, mouse cells, and mouse embryos. We found that loss of TIP60 caused complete cell growth arrest. In the absence of TIP60, chromosomes failed to align in a metaphase plate during mitosis. In some TIP60 deleted cells, endoreplication occurred instead. In contrast, cell survival was not affected. Remarkably, the cell growth arrest caused by loss of TIP60 was independent of the tumor suppressors p53, INK4A and ARF. TIP60 was found to be essential for the acetylation of H2AZ, specifically at lysine 7. The mRNA levels of 6236 human and 8238 mouse genes, including many metabolism genes, were dependent on TIP60. Among the top 50 differentially expressed genes, over 90% were downregulated in cells lacking TIP60, supporting a role for TIP60 as a key co-activator of transcription. We propose a primary role of TIP60 in H2AZ lysine 7 acetylation and transcriptional activation, and that this fundamental role is essential for cell proliferation. Growth arrest independent of major tumor suppressors suggests TIP60 as a potential anti-cancer drug target.
(© 2022. The Author(s).)
Databáze: MEDLINE
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