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SETD1A function is mediated through interaction with mitotic regulators BuGZ/BUB3 in leukemia [RNA-seq]

ABSTRACT: The H3K4 methyltransferase SETD1A plays a crucial role in leukemia cell survival through its non-catalytic FLOS domain mediated recruitment of cyclin K and regulation of DNA damage response genes. In this study, we identify a functional nuclear localization signal and interaction partners for the FLOS domain. Our proteomics analysis against FLOS domain-binding partners reveals that the SETD1A FLOS domain binds mitosis-associated proteins BuGZ/BUB3. Targeted inhibition of both cyclin K and BuGZ/BUB3 binding motifs on SETD1A shows synergistic anti-leukemic effects. BuGZ/BUB3 localize to SETD1A-positive 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 the leukemia cell proliferation. Despite the role of BuGZ/BUB3 at mitotic phase, the cell-cycle specific SETD1A restoration study indicates the roles of SETD1A at G1/S phase of cell cycle. Discovery of this complex indicates the indispensable role of the SETD1A-BuGZ axis in cancer.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE159145 | GEO | 2023/07/29

REPOSITORIES: GEO

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Project description:Cyclin C was cloned as a growth-promoting G1 cyclin, and several studies postulated a role for cyclin C in driving cell proliferation. Moreover, cyclin C, together with its kinase partner, the cyclin-dependent kinase CDK8, is believed to represent an essential component of basal transcriptional machinery where it globally represses gene expression. However, the function of cyclin C in vivo has never been addressed. Here we show that in the living organism cyclin C acts as a haploinsufficient tumor suppressor, through its function of controlling Notch1 oncogene levels. Cyclin C activates an M-bM-^@M-^\orphanM-bM-^@M-^] CDK19 kinase, as well as CDK8 and CDK3. These cyclin C-CDK complexes phosphorylate Notch1 intracellular domain (ICN1), which allows binding of ICN1 to Fbw7 and triggers ICN1 polyubiquitination. Genetic ablation of cyclin C blocks ICN1 phosphorylation, disrupts Fbw7 binding, and decreases ICN1 ubiquitination in vivo, thereby strongly elevating ICN1 levels in several compartments of cyclin C knockout mice. Ablation of cyclin C, or cyclin C heterozygosity collaborate with other oncogenic lesions and accelerate development of T-cell acute lymphoblastic leukemia (T-ALL) in cyclin Cdeficient mice. Furthermore, the locus encoding cyclin C is heterozygously deleted in a significant fraction of human T-ALL, and these tumors express reduced cyclin C levels. In addition, we describe point mutations in human T-ALL tumors that render cyclin C-CDK unable to phosphorylate ICN1. These studies reveal that in sharp contrast to all other cyclin proteins, cyclin C functions as a growth-suppressor in vivo, and suggest that human tumor cells develop different strategies to evade cyclin C inhibitory function. Comparison of wild-type mouse embryonic fibroblasts (n=3 biological replicates) versus cyclin C knockout MEFs (n=3), wild-type mouse embryonic stem cells (n=3) versus cyclin C knockout ESC (n=3), wild-type mouse embryonic brain (n=3) versus cyclin C knockout embryonic brain (n=3)

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SETD1A function is mediated through interaction with mitotic regulators BuGZ/BUB3 in leukemia [RNA-seq]

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