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Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity

ABSTRACT: CARM1 Y149F, Y334F or Y149F/Y334F mutants have decreased activtiy to dimethylate RUNX1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200973 | GEO | 2024/04/03

REPOSITORIES: GEO

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Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity

Project description:Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity

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Biochemical control of CARM1 enzymatic activity by phosphorylation.

Project description:Coactivator-associated arginine methyltransferase 1 (CARM1) is a dual functional coregulator that facilitates transcription initiation by methylation of Arg(17) and Arg(26) of histone H3 and also dictates the subsequent coactivator complex disassembly by methylation of the steroid receptor coactivator family coactivators and p300/cAMP-response element-binding protein-binding protein. However, the regulation of CARM1 enzymatic activity and substrate specificity remains largely unknown. In this study, we report that CARM1 function is regulated by phosphorylation at Ser(217), a residue completely conserved in the type I protein arginine methyltransferase (PRMT) family of enzymes. Comparative analysis of the published CARM1 crystal structures reveals that the hydroxyl group of Ser(217) forms a strong hydrogen bond with the carbonyl oxygen atom of Tyr(154) to lock the cofactor S-adenosylmethionine inside the binding cavity. Phosphorylation of Ser(217) disrupts this hydrogen bond and subsequently abolishes S-adenosylmethionine binding and its methyltransferase activity. Importantly, Tyr(154) is also conserved in the type I PRMT family of enzymes, suggesting a general role of this hydrogen bond in maintaining the holo structure of the type I PRMT catalytic domain. Moreover, we found that phosphorylation at Ser(217) also promoted CARM1 cytoplasmic localization and that this translocation occurred mainly during mitosis. We propose that phosphorylation at Ser(217) serves as a molecular switch for controlling CARM1 enzymatic activity during the cell cycle.

| S-EPMC2794732 | biostudies-literature

CARM1 substrate identification

Project description:The goal of the project was global identification of CARM1 substrates. Arginine methylation landscapes were profiled and compared in wild type and CARM1 knockout cells to determine in vivo substrates of CARM1.

2017-07-03 | PXD005871 | Pride

CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity [RNA-Seq]

Project description:CARM1 is an arginine methyltransferase that asymmetrically dimethylates protein substrates on arginine residues. CARM1 is often overexpressed in cancers and stimulates growth. However, clinically applicable therapeutic strategies based on CARM1 expression in cancer remains to be explored. Here we show that epithelial ovarian cancer is among the cancers with the highest CARM1 amplification rates that predicates a shorter survival. Our unbiased screen show that CARM1-expressing ovarian cancer cells are selectively sensitive to the inhibition of EZH2, another epigenetic regulator that silences its target genes. Inhibition of EZH2 activity using a clinically applicable small molecule inhibitor significantly suppressed the growth of CARM1-expressing ovarian tumors in two xenograft models. The observed selectivity correlates with upregulation of EZH2 target genes in a CARM1-dependent manner. CARM1 promotes EZH2 dependent gene silencing by methylating BAF155 to alter the antagonism between EZH2 and BAF155. Together, these results indicate that pharmacological inhibition of EZH2 is a novel therapeutic strategy for CARM1-expressing cancers.

2018-03-02 | GSE95644 | GEO

CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity [ChIP-Seq]

2018-03-02 | GSE95643 | GEO

The NFIB/CARM1 Axis is a Therapeutic Target for Small Cell Lung Cancer

Project description:We identified NFIB as a CARM1 substrate and showed that this transcription factor utilizes CARM1 as a coactivator. Importantly, NFIB harbors both oncogenic and metastatic activities, and is often overexpressed in small cell lung cancer (SCLC). Using a SCLC mouse model, we show that both CARM1 and the CARM1 methylation site on NFIB are critical for the rapid onset of SCLC. By performing the high-throughput sequecing analysis, we found that CARM1-null and NFIB-R388K mutant mouse SCLC tumors share the ability to regulate chromatin accessbility and have similar gene expression pattern.

2022-02-07 | GSE195843 | GEO

Gene expression profiles of CARM1 overexpression in MCF7

Project description:The goal of this study is to identify ERalpha-target genes affected by overexpression of the histone arginine methyltransferase CARM1 in breast cancer cells. The roles of CARM1 in ERalpha+ breast cancer was not well characterized. Therefore, we created a Dox inducible CARM1 overexpressing MCF7 cell line where CARM1 is overexpressed by 2 fold to determine the created a Dox-inducible CARM1 overexpressing MCF7 cells for evaluation of the global effects of CARM1 on Eralpha-target gene expression. MCF7-tet-on-CARM1 clone 13 were treated under 4 conditions: DMSO; Dox; E2 (10nM); Dox+E2. In Dox+E2 condition, cells were pre-treated with Dox for 5 days before treating with E2 for 4 hours. 3 biological replicates were included and total of 12 samples were analyzed.

2011-06-01 | E-GEOD-26454 | biostudies-arrayexpress

Gene expression profiles of MCF7 with CARM1 knocked down

Project description:The goal of this study is to identify ERalpha-target genes affected by knocking down of the histone arginine methyltransferase CARM1 in MCF7 breast cancer cells. The roles of CARM1 in ERalpha+ breast cancer was not well characterized. Therefore, we created a Dox inducible CARM1 knockingdown MCF7 cell line where CARM1 is decreased to 20% of endogeneous level to determine the created a Dox-inducible CARM1shRNA overexpressing MCF7 cells for evaluation of the global effects of CARM1 on ERalpha-target gene expression. MCF7-tet-on-CARM1shRNA clone 1 were treated under 4 conditions: DMSO; Dox; E2 (10nM); Dox+E2. In Dox+E2 condition, cells were pre-treated with Dox for 5 days before treating with E2 for 4 hours. 3 biological replicates were included and total of 12 samples were analyzed.

2011-06-01 | E-GEOD-26259 | biostudies-arrayexpress

Global tibialis anterior skeletal muscle transcript data from male Carm1 skm-/- (HSAcre Tg/0 x Floxed Carm1) and Carm1 skm+/+ mice (HSAcre 0/0 x Floxed Carm1) on a chow diet.

Project description:Transcript data from tibialis anterior muscle from male muscle-specific Coactivator-Associated Arginine Methyltransferase 1 (Carm1 ) knockout mice (Carm1 skm-/- ) and wild-type mice (Carm1 skm+/+) generated by using the Cre-loxP system (on a C57BL6J/129 background) with HSA-Cre mice (from Jackson laboratories). We used RNA-Seq to detail the effects of muscle-specific loss of Carm1 on the global program of gene expression in tibialis anterior muscle.

2022-08-24 | GSE189351 | GEO

Transcription profiling of mouse embryonic fibroblasts carm1-/- completemented with CARM1 wt were left untreated or were stimulated for 3hours with 10ng/ml mTNFa

Project description:Complemented carm1-/- MEFs with CARM1 wt were left untreated or were stimulated for 3hours with 10ng/ml mTNFa. mTNFa-induced NF-kB dependent gene expression was analyzed on a custom array for specific NF-kB target genes

2009-09-01 | E-MEXP-2020 | biostudies-arrayexpress

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