MLL/SET methyltransferases catalyze methylation of histone 3 lysine 4 and play critical roles in development and cancer. We assessed MLL/SET proteins and found that SETD1A is required for survival of acute myeloid leukemia (AML) cells. Mutagenesis studies and CRISPR-Cas9 domain screening show the enzymatic SET domain is not necessary for AML cell survival but that a newly identified region termed the "FLOS" (functional location on SETD1A) domain is indispensable. FLOS disruption suppresses DNA damage response genes and induces p53-dependent apoptosis. The FLOS domain acts as a cyclin-K-binding site that is required for chromosomal recruitment of cyclin K and for DNA-repair-associated gene expression in S phase. These data identify a connection between the chromatin regulator SETD1A and the DNA damage response that is independent of histone methylation and suggests that targeting SETD1A and cyclin K complexes may represent a therapeutic opportunity for AML and, potentially, for other cancers.

中文翻译：

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SETD1A 的非催化功能调节 Cyclin K 和 DNA 损伤反应。

MLL/SET 甲基转移酶催化组蛋白 3 赖氨酸 4 的甲基化，并在发育和癌症中发挥关键作用。我们评估了 MLL/SET 蛋白，发现 SETD1A 是急性髓性白血病 (AML) 细胞存活所必需的。诱变研究和 CRISPR-Cas9 域筛选表明酶促 SET 域对于 AML 细胞存活不是必需的，但新发现的称为“FLOS”（SETD1A 上的功能位置）域的区域是必不可少的。FLOS 破坏抑制 DNA 损伤反应基因并诱导 p53 依赖性细胞凋亡。FLOS 结构域充当细胞周期蛋白-K 结合位点，该位点是细胞周期蛋白 K 的染色体募集和 S 期 DNA 修复相关基因表达所必需的。