Perlee, Sarah, Kikuchi, Sota, Nakadai, Tomoyoshi, Masuda, Takeshi, Ohtsuki, Sumio, Matsumoto, Makoto, Rahmutulla, Bahityar, Fukuyo, Masaki, Cifani, Paolo, Kentsis, Alex, Roeder, Robert G, Kaneda, Atsushi, Hoshii, Takayuki (October 2023) SETD1A function in leukemia is mediated through interaction with mitotic regulators BuGZ/BUB3. EMBO Reports, 24 (10). e57108. ISSN 1469-221X
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Abstract
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.
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