A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response.
A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response.
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DOI：
10.1016/j.cell.2018.01.032
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发表时间：
2018-02-22
期刊：
影响因子：
64.5
通讯作者：
Armstrong SA
中科院分区：
文献类型：
--
作者：
Hoshii T;Cifani P;Feng Z;Huang CH;Koche R;Chen CW;Delaney CD;Lowe SW;Kentsis A;Armstrong SA
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结构域筛选表明，酶促SET结构域不是AML细胞存活所必需的，但一个新发现的区域，称为SETD1A上的功能位置（Functional Location on SETD1A），是必不可少的。FLOS破坏抑制DNA损伤反应基因，诱导p53依赖性细胞凋亡。FLOS结构域作为细胞周期蛋白K的结合位点，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。这些数据确定了染色质调节剂SETD1A与独立于组蛋白甲基化的DNA损伤反应之间的联系，并表明靶向SETD1A和Cyclin K复合物可能为AML和潜在的其他癌症提供治疗机会。H3K4甲基转移酶SETD1A独立于其酶活性，通过调节DNA损伤反应促进白血病细胞存活。
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, showed 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 other cancers. Independent of its enzymatic activity, H3K4 methyltransferase SETD1A promotes leukemic cell survival by regulating DNA damage response.
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