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A non-catalytic function of SETD1A regulates Cyclin K and the DNA damage response [ChIP-seq]

ABSTRACT: We assessed MLL/SET proteins and found that SETD1A is required for survival of acute myeloid leukemia (AML) cells

ORGANISM(S): Mus musculus

PROVIDER: GSE108613 | GEO | 2018/02/01

REPOSITORIES: GEO

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A non-catalytic function of SETD1A regulates Cyclin K and the DNA damage response [RNA-seq]

Project description: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.

2018-02-01 | GSE108614 | GEO

SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia [RNA-seq]

Project description:Histone methyltransferase SETD1A is critical for acute myeloid leukemia (AML) cell survival, but the molecular mechanism driving SETD1A gene regulation remains elusive. To delineate the role of SETD1A, we utilize a protein degrader technology to induce rapid SETD1A degradation in AML cell lines. SETD1A degradation results in immediate downregulation of transcripts associated with DNA repair and heme biosynthesis pathways. CRISPR-based functional analyses and metabolomics revealed an essential role of SETD1A to maintain mitochondrial respiration in AML cells. These SETD1A targets are enriched in head-to-head (H2H) genes. SETD1A degradation disturbs a non-enzymatic SETD1A domain-dependent cyclin K function, increases the mono-Ser5P RNA polymerase II (RNAP2) at TSS, and induces the promoter-proximal pausing of RNAP2 in a strand-specific manner. This study reveals a non-enzymatic role for SETD1A in transcriptional pause release and provides insight into the mechanism of RNAP2 pausing and its function in cancer.

2022-12-09 | GSE189893 | GEO

SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia [ChIP-Seq]

2022-12-09 | GSE190994 | GEO

A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response.

Project description: Not available

| S-EPMC6052445 | biostudies-literature

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

Project description: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.

2023-07-29 | GSE159145 | GEO

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

2023-07-29 | GSE159144 | GEO

A non-catalytic function of SETD1A regulates Cyclin K and the DNA damage response

Project description:A non-catalytic function of SETD1A regulates Cyclin K and the DNA damage response

| PRJNA427819 | ENA

A non-catalytic function of SETD1A regulates Cyclin K and the DNA damage response

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-02-01 | GSE108615 | GEO

A non-catalytic function of SETD1A regulates Cyclin K and the DNA damage response [RNA-seq]

Project description:A non-catalytic function of SETD1A regulates Cyclin K and the DNA damage response [RNA-seq]

| PRJNA427821 | ENA