SUV39 SET domains mediate crosstalk of heterochromatic histone marks.
SUV39 SET domains mediate crosstalk of heterochromatic histone marks.
复制标题
DOI：
10.7554/elife.62682
复制
发表时间：
2021-09-15
期刊：
影响因子：
7.7
通讯作者：
Schalch T
中科院分区：
文献类型：
--
作者：
Stirpe A;Guidotti N;Northall SJ;Kilic S;Hainard A;Vadas O;Fierz B;Schalch T
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。人们对如何调节这些酶将特定基因组区域标记为异染色质知之甚少。 Clr4 是裂殖酵母裂殖酵母中唯一的 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 甲基化中发挥关键作用。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且紧密地结合，从而将酶刺激超过 250 倍。破坏这一机制的突变会导致 H3K9me2/3 丢失并消除异染色质沉默，类似于 clr4 缺失。与哺乳动物 SET 结构域蛋白的比较表明，Clr4 SET 结构域含有 H3K14ub 的保守传感器，该传感器介导异染色质形成的许可。
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.