The SUV39 class of methyltransferase enzymes deposits histone H3 lysine 9 di- and trimethylation (H3K9me2/3), the hallmark of constitutive heterochromatin. How these enzymes are regulated to mark specific genomic regions as heterochromatic is poorly understood. Clr4 is the sole H3K9me2/3 methyltransferase in the fission yeast Schizosaccharomyces pombe, and recent evidence suggests that ubiquitination of lysine 14 on histone H3 (H3K14ub) plays a key role in H3K9 methylation. However, the molecular mechanism of this regulation and its role in heterochromatin formation remain to be determined. Our structure-function approach shows that the H3K14ub substrate binds specifically and tightly to the catalytic domain of Clr4, and thereby stimulates the enzyme by over 250-fold. Mutations that disrupt this mechanism lead to a loss of H3K9me2/3 and abolish heterochromatin silencing similar to clr4 deletion. Comparison with mammalian SET domain proteins suggests that the Clr4 SET domain harbors a conserved sensor for H3K14ub, which mediates licensing of heterochromatin formation.

中文翻译：

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SUV39 SET 域介导异色组蛋白标记的串扰

SUV39 类甲基转移酶沉积组蛋白 H3 赖氨酸 9 二甲基化和三甲基化 (H3K9me2/3)，这是组成型异染色质的标志。这些酶是如何被调节以将特定基因组区域标记为异染色质的，我们知之甚少。Clr4 是裂殖酵母粟酒裂殖酵母中唯一的 H3K9me2/3 甲基转移酶，最近的证据表明，组蛋白 H3 (H3K14ub) 上赖氨酸 14 的泛素化在 H3K9 甲基化中起关键作用。然而，这种调节的分子机制及其在异染色质形成中的作用仍有待确定。我们的结构-功能方法表明 H3K14ub 底物与 Clr4 的催化结构域特异性紧密结合，从而将酶刺激 250 倍以上。破坏这种机制的突变会导致 H3K9me2/3 的丢失并消除类似于clr4缺失的异染色质沉默。与哺乳动物 SET 域蛋白的比较表明 Clr4 SET 域包含一个保守的 H3K14ub 传感器，它介导了异染色质形成的许可。