The disordered regions of the methyltransferase SETD2 govern its function by regulating its proteolysis and phase separation.
TL;DR: In this paper, the authors show that disordered regions can reduce the half-life of the yeast homolog Set2 in mammalian cells as well as in yeast, demonstrating the importance of intrinsic structural features in regulating protein half life.
About: This article is published in Journal of Biological Chemistry.The article was published on 2021-09-01 and is currently open access. It has received 5 citations till now. The article focuses on the topics: Protein degradation & Histone H3.
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TL;DR: In this article, the authors describe the mode of interaction between hnRNP L and LL with the methyltransferase SETD2 and demonstrate that for the interaction to occur, a leucine pair within a highly conserved stretch of SetD2 insert their side chains in hydrophobic pockets formed by hnRN L RRM2.
Abstract: The RNA recognition motif (RRM) binds to nucleic acids as well as proteins. More than one such domain is found in the pre-mRNA processing hnRNP proteins. While the mode of RNA recognition by RRMs is known, the molecular basis of their protein interaction remains obscure. Here we describe the mode of interaction between hnRNP L and LL with the methyltransferase SETD2. We demonstrate that for the interaction to occur, a leucine pair within a highly conserved stretch of SETD2 insert their side chains in hydrophobic pockets formed by hnRNP L RRM2. Notably, the structure also highlights that RRM2 can form a ternary complex with SETD2 and RNA. Remarkably, mutating the leucine pair in SETD2 also results in its reduced interaction with other hnRNPs. Importantly, the similarity that the mode of SETD2-hnRNP L interaction shares with other related protein-protein interactions reveals a conserved design by which splicing regulators interact with one another.
10 citations
TL;DR: The role of Set2/SETD2 in the regulation of H3K36 methylation was discussed in this article , where Set2 methylates non-histone substrates such as α-tubulin which may promote genome stability and contribute to the tumor-suppressor function of SETD2.
Abstract: Histone modifying enzymes play critical roles in many key cellular processes and are appealing proteins for targeting by small molecules in disease. However, while the functions of histone modifying enzymes are often linked to epigenetic regulation of the genome, an emerging theme is that these enzymes often also act by non-catalytic and/or non-epigenetic mechanisms. SETD2 (Set2 in yeast) is best known for associating with the transcription machinery and methylating histone H3 on lysine 36 (H3K36) during transcription. This well-characterized molecular function of SETD2 plays a role in fine-tuning transcription, maintaining chromatin integrity, and mRNA processing. Here we give an overview of the various molecular functions and mechanisms of regulation of H3K36 methylation by Set2/SETD2. These fundamental insights are important to understand SETD2's role in disease, most notably in cancer in which SETD2 is frequently inactivated. SETD2 also methylates non-histone substrates such as α-tubulin which may promote genome stability and contribute to the tumor-suppressor function of SETD2. Thus, to understand its role in disease, it is important to understand and dissect the multiple roles of SETD2 within the cell. In this review we discuss how histone methylation by Set2/SETD2 has led the way in connecting histone modifications in active regions of the genome to chromatin functions and how SETD2 is leading the way to showing that we also have to look beyond histones to truly understand the physiological role of an 'epigenetic' writer enzyme in normal cells and in disease.
7 citations
TL;DR: The SET domain-containing 2 (SETD2) deficiency is associated with cancer occurrence and progression by regulating autophagy flux, general metabolic activity, and replication fork speed as mentioned in this paper .
Abstract: SET domain-containing 2 (SETD2) is a lysine methyltransferase that catalyzes histone H3 lysine36 trimethylation (H3K36me3) and has been revealed to play important roles in the regulation of transcriptional elongation, RNA splicing, and DNA damage repair. SETD2 mutations have been documented in several cancers, including clear cell renal cell carcinoma (ccRCC). SETD2 deficiency is associated with cancer occurrence and progression by regulating autophagy flux, general metabolic activity, and replication fork speed. Therefore, SETD2 is considered a potential epigenetic therapeutic target and is the subject of ongoing research on cancer-related diagnosis and treatment. This review presents an overview of the molecular functions of SETD2 in H3K36me3 regulation and its relationship with ccRCC, providing a theoretical basis for subsequent antitumor therapy based on SETD2 or H3K36me3 targets.
1 citations
TL;DR: It is shown that SETD2 accumulation results in a non-canonical deposition of the functionally important H3K36me3 histone mark, which includes its reduced enrichment over gene bodies and exons.
Abstract: The methyltransferase SETD2 regulates cryptic transcription, alternative splicing, and the DNA damage response. It is mutated in a variety of cancers and is believed to be a tumor suppressor. Counterintuitively, despite its important role, SETD2 is robustly degraded by the proteasome keeping its levels low. Here we show that SETD2 accumulation results in a non-canonical deposition of the functionally important H3K36me3 histone mark, which includes its reduced enrichment over gene bodies and exons. This perturbed epigenetic landscape is associated with widespread changes in transcription and alternative splicing. Strikingly, contrary to its role as a tumor suppressor, excessive SETD2 results in the upregulation of cell cycle-associated pathways. This is also reflected in phenotypes of increased cell proliferation and migration. Thus, the regulation of SETD2 levels through its proteolysis is important to maintain its appropriate function, which in turn regulates the fidelity of transcription and splicing-related processes.
1 citations
TL;DR: In this paper , a CRISPR/Cas9-mediated SETD2 knockout Met-5A mesothelial cells (Met-5ASETD2-KO ) were established and exposed with crocidolite, an amphibole asbestos.
Abstract: Asbestos is fibrous silicate mineral exhibiting biopersistence and carcinogen property and contribute to mesothelioma. Despite the concept of gene-environmental interaction in pathogenesis of mesothelioma, the possible pathophysiological changes of mesothelial cells simultaneously with SETD2 loss and asbestos exposure remains obscure. Herein, CRISPR/Cas9-mediated SETD2 knockout Met-5A mesothelial cells (Met-5ASETD2-KO ) were established and exposed with crocidolite, an amphibole asbestos. Cell viability of Met-5ASETD2-KO appeared to dramatically decrease with ≥ 2.5 μg/cm2 crocidolite exposure as compared to Met-5A, although no cytotoxicity and apoptosis changes of Met-5ASETD2-KO and Met-5A was evident with 1.25 μg/cm2 crocidolite exposure for 48 h. RNA sequencing uncovered top 50 differentially expressed genes (DEGs) between 1.25 μg/cm2 crocidolite exposed Met-5ASETD2-KO (Cro-Met-5ASETD2-KO ) and 1.25 μg/cm2 crocidolite exposed Met-5A (Cro-Met-5A), and ITGA4, THBS2, MYL7, RAC2, CADM1, and CLDN11 appeared to be the primary DEGs involved with adhesion in GO and KEGG analysis. Cro-Met-5ASETD2-KO had strong migration but mild adhesion behavior as compared to Cro-Met-5A. Additionally, crocidolite tended to increase migration of Met-5ASETD2-KO but inhibited migration of Met-5A when compared to their corresponding cells without crocidolite exposure, although no further adhesion property changes was evident for both cells in response to crocidolite. Therefore, crocidolite may affect adhesion-related gene expression and modify adhesion and migration behavior for SETD2-depleted Met-5A, which could provide preliminary insight regarding the potential role of SETD2 in cell behavior of asbestos-related malignant mesothelial cell.
References
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TL;DR: This review discusses recent information on functions and mechanisms of the ubiquitin system and focuses on what the authors know, and would like to know, about the mode of action of ubi...
Abstract: The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Abnormalities in ubiquitin-mediated processes have been shown to cause pathological conditions, including malignant transformation. In this review we discuss recent information on functions and mechanisms of the ubiquitin system. Since the selectivity of protein degradation is determined mainly at the stage of ligation to ubiquitin, special attention is focused on what we know, and would like to know, about the mode of action of ubiquitin-protein ligation systems and about signals in proteins recognized by these systems.
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TL;DR: An update to the SWISS-MODEL server is presented, which includes the implementation of a new modelling engine, ProMod3, and the introduction a new local model quality estimation method, QMEANDisCo.
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Abstract: We describe a largely unbiased method for rapid and large-scale proteome analysis by multidimensional liquid chromatography, tandem mass spectrometry, and database searching by the SEQUEST algorithm, named multidimensional protein identification technology (MudPIT). MudPIT was applied to the proteome of the Saccharomyces cerevisiae strain BJ5460 grown to mid-log phase and yielded the largest proteome analysis to date. A total of 1,484 proteins were detected and identified. Categorization of these hits demonstrated the ability of this technology to detect and identify proteins rarely seen in proteome analysis, including low-abundance proteins like transcription factors and protein kinases. Furthermore, we identified 131 proteins with three or more predicted transmembrane domains, which allowed us to map the soluble domains of many of the integral membrane proteins. MudPIT is useful for proteome analysis and may be specifically applied to integral membrane proteins to obtain detailed biochemical information on this unwieldy class of proteins.
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