Department of Biochemistry & Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Department of Genetics, Harvard Medical School, Harvard University, Boston, MA 02115, USA.
Nucleic Acids Res. 2018 Feb 16;46(3):1331-1344. doi: 10.1093/nar/gkx1276.
Methylation of histone H3 lysine 36 (H3K36me) by yeast Set2 is critical for the maintenance of chromatin structure and transcriptional fidelity. However, we do not know the full range of Set2/H3K36me functions or the scope of mechanisms that regulate Set2-dependent H3K36 methylation. Here, we show that the APC/CCDC20 complex regulates Set2 protein abundance during the cell cycle. Significantly, absence of Set2-mediated H3K36me causes a loss of cell cycle control and pronounced defects in the transcriptional fidelity of cell cycle regulatory genes, a class of genes that are generally long, hence highly dependent on Set2/H3K36me for their transcriptional fidelity. Because APC/C also controls human SETD2, and SETD2 likewise regulates cell cycle progression, our data imply an evolutionarily conserved cell cycle function for Set2/SETD2 that may explain why recurrent mutations of SETD2 contribute to human disease.
酵母 Set2 对组蛋白 H3 赖氨酸 36（H3K36me）的甲基化对于维持染色质结构和转录保真度至关重要。然而，我们并不知道 Set2/H3K36me 的全部功能，也不知道调节 Set2 依赖性 H3K36 甲基化的机制范围。在这里，我们表明 APC/CCDC20 复合物在细胞周期中调节 Set2 蛋白的丰度。重要的是，缺乏 Set2 介导的 H3K36me 会导致细胞周期失控，并显著影响细胞周期调节基因的转录保真度，这些基因通常较长，因此高度依赖 Set2/H3K36me 来保证其转录保真度。由于 APC/C 还控制人类 SETD2，并且 SETD2 同样调节细胞周期进程，我们的数据表明 Set2/SETD2 具有保守的细胞周期功能，这可能解释了为什么 SETD2 的反复突变会导致人类疾病。
