SETD1A在白血病中的功能是通过与有丝分裂调节因子BuGZ/BUB3的相互作用介导的。
SETD1A function in leukemia is mediated through interaction with mitotic regulators BuGZ/BUB3.
发表日期：2023 Aug 03
作者：
Sarah Perlee, Sota Kikuchi, Tomoyoshi Nakadai, Takeshi Masuda, Sumio Ohtsuki, Makoto Matsumoto, Bahityar Rahmutulla, Masaki Fukuyo, Paolo Cifani, Alex Kentsis, Robert G Roeder, Atsushi Kaneda, Takayuki Hoshii
来源：
EMBO REPORTS
摘要：
H3K4甲基转移酶 SETD1A 通过其非催化 FLOS 结构域介导的 Cyclin K 招募并调节 DNA 损伤应答基因，在白血病细胞存活中发挥重要作用。在本研究中，我们确定了 FLOS 结构域内的功能性核定位信号以及与其相互作用的蛋白质伴侣。我们对 FLOS 结构域结合伴侣进行的筛选揭示了 SETD1A FLOS 结构域与有丝分裂相关蛋白质 BuGZ/BUB3 结合。抑制 SETD1A 中 Cyclin K 和 BuGZ/BUB3 结合位点表现出协同的抗白血病效应。BuGZ/BUB3 定位于与 SETD1A 结合的启动子-TSS 区域以及 SETD1A 靶基因旁边的 SETD1A 阴性 H3K4me1 阳性增强子区域。BuGZ 的 GLEBS 结构域和本质无序区域在 SETD1A 结合和白血病细胞增殖中都起到了必要的作用。细胞周期特异性的 SETD1A 恢复实验表明，在细胞周期的 G1/S 期，SETD1A 的表达促进了白血病细胞中 DNA 损伤应答基因的表达和细胞周期进展。© 2023 The Authors.
The H3K4 methyltransferase SETD1A plays a crucial role in leukemia cell survival through its noncatalytic FLOS domain-mediated recruitment of cyclin K and regulation of DNA damage response genes. In this study, we identify a functional nuclear localization signal in and interaction partners of the FLOS domain. Our screen for FLOS domain-binding partners reveals that the SETD1A FLOS domain binds mitosis-associated proteins BuGZ/BUB3. Inhibition of both cyclin K and BuGZ/BUB3-binding motifs in SETD1A shows synergistic antileukemic effects. BuGZ/BUB3 localize to SETD1A-bound promoter-TSS regions and SETD1A-negative H3K4me1-positive enhancer regions adjacent to SETD1A target genes. The GLEBS motif and intrinsically disordered region of BuGZ are required for both SETD1A-binding and leukemia cell proliferation. Cell-cycle-specific SETD1A restoration assays indicate that SETD1A expression at the G1/S phase of the cell cycle promotes both the expression of DNA damage response genes and cell cycle progression in leukemia cells.© 2023 The Authors.