Histone-modifying enzymes can regulate DNA damage-induced apoptosis through modulation of p53 function. Here, we show that, in p53-deficient tumor cells, Set9 and LSD1 regulate DNA damage-induced cell death in a manner opposite to that observed in p53(+/+) cells, via modulation of E2F1 stabilization. Set9 methylates E2F1 at lysine-185, which prevents E2F1 accumulation during DNA damage and activation of its proapoptotic target gene p73. This methyl mark is removed by LSD1, which is required for E2F1 stabilization and apoptotic function. The molecular mechanism involves crosstalks between lysine methylation and other covalent modifications that affect E2F1 stability. Methylation at lysine-185 inhibits acetylation and phosphorylation at distant positions and, in parallel, stimulates ubiquitination and degradation of the protein. The findings illustrate that the function of methyltransferases can have opposing biological outcomes depending on the specificity of transcription factor targets.
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