Human SETD2 is the unique histone methyltransferase that generates H3K36 trimethylation (H3K36me3), an epigenetic mark that plays a key role in normal hematopoiesis. Interestingly, recurrent inactivating mutations of SETD2 and aberrant H3K36me3 are increasingly reported to be involved in hematopoietic malignancies. Benzene (BZ) is a ubiquitous environmental pollutant and carcinogen that causes leukemia. The leukemogenic properties of BZ depend on its biotransformation in the bone marrow into oxidative metabolites, in particular 1,4-benzoquinone (BQ). This hematotoxic metabolite can form DNA and protein adducts that result in the damage and the alteration of cellular processes. Recent studies suggest that BZ-dependent leukemogenesis could depend on epigenetic perturbations, notably aberrant histone methylation. We investigated whether H3K36 trimethylation by SETD2 could be impacted by BZ and its hematotoxic metabolites. Herein, we show that BQ, the major leukemogenic metabolite of BZ, inhibits irreversibly the human histone methyltransferase SETD2, resulting in decreased H3K36me3. Our mechanistic studies further indicate that the BQ-dependent inactivation of SETD2 is due to covalent binding of BQ to reactive Zn-finger cysteines within the catalytic domain of the enzyme. The formation of these quinoprotein adducts results in loss of enzyme activity and protein crosslinks/oligomers. Experiments conducted in hematopoietic cells confirm that exposure to BQ results in the formation of SETD2 crosslinks/oligomers and concomitant loss of H3K36me3 in cells. Taken together, our data indicate that BQ, a major hematotoxic metabolite of BZ, could contribute to BZ-dependent leukemogenesis by perturbing the functions of SETD2, a histone lysine methyltransferase of hematopoietic relevance.

中文翻译：

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苯血液毒性和反应性代谢物 1,4-苯醌会损害含有 2 的组蛋白甲基转移酶 SET 结构域 (SETD2) 的活性并导致异常组蛋白 H3 赖氨酸 36 三甲基化 (H3K36me3)

人类 SETD2 是独特的组蛋白甲基转移酶，可产生 H3K36 三甲基化 (H3K36me3)，这是一种在正常造血中起关键作用的表观遗传标记。有趣的是，越来越多的报道称 SETD2 和异常 H3K36me3 的反复失活突变与造血系统恶性肿瘤有关。苯 (BZ) 是一种普遍存在的环境污染物和致癌物质，可导致白血病。BZ 的致白血病特性取决于其在骨髓中生物转化为氧化代谢物，特别是 1,4-苯醌 (BQ)。这种血液毒性代谢物可以形成 DNA 和蛋白质加合物，导致细胞过程的损伤和改变。最近的研究表明，BZ 依赖性白血病发生可能取决于表观遗传扰动，特别是异常的组蛋白甲基化。我们研究了 SETD2 引起的 H3K36 三甲基化是否会受到 BZ 及其血液毒性代谢物的影响。在此，我们表明 BQ 是 BZ 的主要致白血病代谢物，不可逆地抑制人组蛋白甲基转移酶 SETD2，导致 H3K36me3 减少。我们的机理研究进一步表明，SETD2 的 BQ 依赖性失活是由于 BQ 与酶催化结构域内的反应性锌指半胱氨酸共价结合。这些醌蛋白加合物的形成导致酶活性和蛋白质交联/寡聚体的丧失。在造血细胞中进行的实验证实，暴露于 BQ 会导致细胞中 SETD2 交联/寡聚体的形成和 H3K36me3 的伴随损失。总之，我们的数据表明 BQ，BZ 的主要血液毒性代谢物，