Protein arginine methyltransferases: Evolution and assessment of their pharmacological and therapeutic potential

Krause, Christopher D.; Yang, Zhihong; Kim, Young-Sun; Lee, Jin-Hyung; Cook, Jeffry R.; Pestka, Sidney

doi:10.1016/j.pharmthera.2006.06.007

Cited by 246 publications

(245 citation statements)

References 116 publications

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“…31,34 Clearly, new approaches are needed. So far, several lysine and arginine methyl-transferases 35,36 have been identified in humans, many of which have been associated with cancerogenesis. [37][38][39] Targeting HMT in cancer may represent a promising approach.…”

Section: Discussionmentioning

confidence: 99%

Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1

et al. 2011

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Epigenetic deregulation is involved in acute myeloid leukemia (AML) pathogenesis and epigenetic targeting drugs are in clinical trial. Since the first results with histone-deacetylase inhibitors in AML are controversial, novel single and combined treatments need to be explored. It is tempting to combine chromatin-targeting drugs. SUV39H1, the main methyl-transferase for lysine 9 tri-methylation on histone H3, interacts with oncogenes involved in AML and acts as a transcriptional repressor for hematopoietic differentiation and immortalization. We report here that pharmacological inhibition of SUV39H1 by chaetocin induces apoptosis in leukemia cell lines in vitro and primary AML cells ex vivo, and that it interferes with leukemia growth in vivo. Chaetocin treatment upregulates reactive oxygen species (ROS) production as well as the transcription of death-receptor-related genes, in a ROS-dependent manner, leading to death receptor-dependent apoptosis. In addition to its direct inhibition by chaetocin, SUV39H1 is indirectly modulated by chaetocin-induced ROS. Accordingly, chaetocin potentiates other anti-AML drugs, in a ROS-dependent manner. The decryption of a dual mechanism of action against AML involving both direct and indirect SUV39H1 modulation represents an innovative read-out for the anticancer activity of chaetocin and for its synergy with other anti-AML drugs, suggesting new therapeutic combination strategies in AML.

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Section: Discussionmentioning

confidence: 99%

Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1

et al. 2011

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“…(residues 140-480 of mCARM1 in complex with SAH) will be used as reference for the further analysis and discussion of the catalytic domain of mCARM1. The core catalytic domain of CARM1 (residues 150-470) is very well conserved in sequence among all PRMTs (for recent reviews, see Cheng et al, 2005;Krause et al, 2007) and was therefore expected to be similar in structure with the already known structures of rat PRMT1 (PDB entries 1OR8, 1ORI and 1ORH) (Zhang and Cheng, 2003), rat PRMT3 (PDB entry 1F3L) (Zhang et al, 2000) and yeast RMT1/Hmt1 (Weiss et al, 2000; Figure 3). The catalytic module of CARM1 is indeed folded into two domains connected by a conserved cis-proline residue (Pro288) and divided into four parts (Figure 4).…”

Section: Resultsmentioning

confidence: 91%

“…PRMTs have been implicated in a variety of biological processes, such as regulation of transcription, translation and DNA repair (Bedford and Richard, 2005;Pahlich et al, 2006;Krause et al, 2007). PRMTs transfer the methyl group from S-adenosyl-L-methionine (SAM, also known as AdoMet) to the side chain nitrogens of arginine residues to form methylated arginine derivatives and S-adenosyl-L-homocysteine (SAH, also known as AdoHcy).…”

Section: Introductionmentioning

confidence: 99%

Functional insights from structures of coactivator-associated arginine methyltransferase 1 domains

Cavarelli¹,

Troffer-Charlier²,

Hassenboehler³

et al. 2008

Acta Cryst Sect A

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Coactivator-associated arginine methyltransferase 1 (CARM1), a protein arginine methyltransferase recruited by several transcription factors, methylates a large variety of proteins and plays a critical role in gene expression. We report, in this paper, four crystal structures of isolated modules of CARM1. The 1.7 Å crystal structure of the N-terminal domain of CARM1 reveals an unexpected PH domain, a scaffold frequently found to regulate protein-protein interactions in a large variety of biological processes. Three crystal structures of the CARM1 catalytic module, two free and one cofactor-bound forms (refined at 2.55 Å , 2.4 Å and 2.2 Å , respectively) reveal large structural modifications including disorder to order transition, helix to strand transition and active site modifications. The N-terminal and the C-terminal end of CARM1 catalytic module contain molecular switches that may inspire how CARM1 regulates its biological activities by protein-protein interactions.

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“…[59][60][61][62] Type I PRMTs catalyze the transfer of the methyl group from S-adenosyl-L-methionine (AdoMet, SAM) to the guanidino nitrogen atoms of arginine residues to produce ω-N G monomethylarginines (MMA) and ω-N G , N G -asymmetric dimethylarginines (ADMA). Type II PRMTs catalyze the formation of MMA and ω-N G ,N 'G -symmetric dimethylarginines (SDMA).…”

Section: B Histone Arginine Methyltransferasesmentioning

confidence: 99%

“…37,63,64 Many PRMTs act as nuclear receptor coactivators, which implicates PRMTs as potential targets in the treatment of hormone-dependent tumors. 62 PRMT1 is a component of the MLL complex, and required for leukemogenic transformation. 65,66 PRMT1 interacts with the interferon-alpha receptor.…”

Section: B Histone Arginine Methyltransferasesmentioning

confidence: 99%

Chemical and biochemical approaches in the study of histone methylation and demethylation

Luo

Wang

et al. 2010

Med. Res. Rev.

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Histone methylation represents one of the most critical epigenetic events in DNA function regulation in eukaryotic organisms. Classic molecular biology and genetics tools provide significant knowledge about mechanisms and physiological roles of histone methyltransferases and demethylases in various cellular processes. In addition to this stream line, development and application of chemistry and chemistry-related techniques are increasingly involved in biological study, and provide information otherwise difficulty to obtain by standard molecular biology methods. Herein, we review recent achievements and progress in developing and applying chemical and biochemical approaches in the study of histone methylation, including chromatin immunoprecipitation (ChIP), chemical ligation, mass spectrometry (MS), biochemical assays, and inhibitor development. These technological advances allow histone methylation to be studied from genome-wide level to molecular and atomic levels. With ChIP technology, information can be obtained about precise mapping of histone methylation patterns at specific promoters, genes or other genomic regions. MS is particularly useful in detecting and analyzing methylation marks in histone and nonhistone protein substrates. Chemical approaches that permit site-specific incorporation of methyl groups into histone proteins greatly facilitate the investigation of the biological impacts of methylation at individual modification sites. Discovery and design of selective organic inhibitors of histone methyltransferases and demethylases provide chemical probes to interrogate methylation-mediated cellular pathways. Overall, these chemistry-related technological advances have greatly improved our understanding of the biological functions of histone methylation in normal physiology and diseased states, and also are of great potential to translate basic epigenetics research into diagnostic and therapeutic application in the clinic.

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Protein arginine methyltransferases: Evolution and assessment of their pharmacological and therapeutic potential

Cited by 246 publications

References 116 publications

Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1

Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1

Functional insights from structures of coactivator-associated arginine methyltransferase 1 domains

Chemical and biochemical approaches in the study of histone methylation and demethylation

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