SETD1A function in leukemia is mediated through interaction with mitotic regulators BuGZ/BUB3

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.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > Cyclins diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > cancer > cancer types > leukemia organs, tissues, organelles, cell types and functions > organelles, types and functions > mitosis organs, tissues, organelles, cell types and functions > organelles, types and functions organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types diseases & disorders > cancer > cancer types
CSHL Authors:	Cifani, Paolo
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	9 October 2023
Date Deposited:	22 Dec 2023 13:38
Last Modified:	10 Jan 2024 20:53
PMCID:	PMC10561176
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41360

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