The SUV39H1 Protein Lysine Methyltransferase Methylates Chromatin Proteins Involved in Heterochromatin Formation and VDJ Recombination

Kudithipudi, Srikanth; Schuhmacher, Maren Kirstin; Kebede, Adam Fiseha; Jeltsch, Albert

doi:10.1021/acschembio.6b01076

Cited by 31 publications

(38 citation statements)

References 58 publications

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“…Slight reduction in HupB methylation was observed in 6XHis‐HupB K214A mutant but was not statistically significant in contrast to the significant decrease in the level of HupB methylation observed for 6XHis‐HupB K138A mutant (Fig EV3B and C). This indicated that SUV39H1 was methylating HupB at lysine present at 138 position and within the motif similar to the one present around H3K9 in histone H3 and the defined SUV39H1 specificity profile (Kudithipudi et al , ).…”

Section: Resultsmentioning

confidence: 93%

“…While the central part of the motif “ARK” was present in several proteins, the TK–ARK—KAP motif was present only in the M. tuberculosis HupB protein (amino acids 132–144, Figs E and EV3A). In addition, a recent study has identified the specificity profile of SUV39H1 and characterized non‐histone protein targets of SUV39H1 (Kudithipudi et al , ). The amino acid profile of M. tuberculosis HupB around K138 was also found to be similar to the SUV39H1 profile with an invariant arginine at −1 position and a lysine at −4 position (from K138; Kudithipudi et al , ).…”

Section: Resultsmentioning

confidence: 99%

“…HupB is a histone‐like protein from mycobacteria. Moreover, K138, the lysine in HupB that was found to be methylated by SUV39H1, is present within a sequence motif that is almost same as the one that encompasses H3K9 and is present in a sequence motif that is similar to specificity profile of SUV39H1 (Kudithipudi et al , ). Interestingly, mycobacteria have two more histone‐like protein, HNS and HBHA.…”

Section: Discussionmentioning

confidence: 99%

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Histone methyltransferase SUV 39H1 participates in host defense by methylating mycobacterial histone‐like protein HupB

et al. 2017

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Host cell defense against an invading pathogen depends upon various multifactorial mechanisms, several of which remain undiscovered. Here, we report a novel defense mechanism against mycobacterial infection that utilizes the histone methyltransferase, SUV39H1. Normally, a part of the host chromatin, SUV39H1, was also found to be associated with the mycobacterial bacilli during infection. Its binding to bacilli was accompanied by trimethylation of the mycobacterial histone-like protein, HupB, which in turn reduced the cell adhesion capability of the bacilli. Importantly, SUV39H1-mediated methylation of HupB reduced the mycobacterial survival inside the host cell. This was also true in mice infection experiments. In addition, the ability of mycobacteria to form biofilms, a survival strategy of the bacteria dependent upon cell-cell adhesion, was dramatically reduced in the presence of SUV39H1. Thus, this novel defense mechanism against mycobacteria represents a surrogate function of the epigenetic modulator, SUV39H1, and operates by interfering with their cell-cell adhesion ability.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Histone methyltransferase SUV 39H1 participates in host defense by methylating mycobacterial histone‐like protein HupB

et al. 2017

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“…In humans, the SUV39 family proteins, namely SUV39H1 (KMT1A), SUV39H2 (KMT1B), SETDB1 (KMT1E), SETDB2 (KMT1F), G9A (EHMT2) and G9a-like protein (GLP1), contain pre-SET (N-SET) and post-SET (C-SET) domains besides the SET domain and mediate H3K9 methylation [3][4][5][6]. SUV39H2 is primarily responsible for di-and tri-methylation of H3K9; H3K9me3 is associated with heterochromatin organization at pericentric and telomeric repeats, transcriptional repression, and epigenetic silencing of the domains in euchromatin [1,[7][8][9][10][11][12]. SUV39H2 possesses three protein isoforms and its exon 3 could affect its histone methyltransferases (HMTases) activity, stability, and sub-nuclear localization [13].…”

Section: Introductionmentioning

confidence: 99%

The Oncogenic Potential of SUV39H2: A Comprehensive and Perspective View

Li¹,

Zheng²,

Yang³

2019

J. Cancer

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Epigenetic modifications at the histone level have attracted significant attention because of their roles in tumorigenesis. Suppressor of variegation 3-9 homolog 2 (SUV39H2, also known as KMT1B) is a member of the SUV39 subfamily of lysine methyltransferases (KMTs) that plays a significant role in histone H3-K9 di-/tri-methylation, transcriptional regulation and cell cycle. Overexpressions of SUV39H2 at gene, mRNA and protein levels are known to be associated with a range of cancers: leukemia, lymphomas, lung cancer, breast cancer, colorectal cancer, gastric cancer, hepatocellular cancer and so on. Accumulating evidence indicates that SUV39H2 acts as an oncogene and contributes to the initiation and progression of cancers. It could, therefore, be a promising target for anti-cancer treatment. In this review, we focus on the dysregulation of SUV39H2 in cancers, including its clinical prognostic predictor role, molecular mechanism involved in cancer occurrence and development, relevant inhibitors against cancer, and its epigenetic modification interaction with immunotherapy. A better understanding of the SUV39H2 will be beneficial to the development of molecular-targeted therapies in cancer.

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“…In our workflow, the substrate specificity of SMYD2 is analyzed by methylation of peptide arrays to identify additional non‐histone targets in a systematic manner. Different studies already showed that the analysis of the specificity profiles of PKMTs is a powerful method to investigate their substrate recognition and based on this discover novel substrates . With this approach, we identified 32 novel peptide substrates of SMYD2 with validated methylation sites.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the Substrate Specificity of the SMYD2 Protein Lysine Methyltransferase and Discovery of Novel Non‐Histone Substrates

et al. 2019

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The SMYD2 protein lysine methyltransferase methylates various histone and non‐histone proteins and is overexpressed in several cancers. Using peptide arrays, we investigated the substrate specificity of the enzyme, revealing a recognition of leucine (or weaker phenylalanine) at the −1 peptide site and disfavor of acidic residues at the +1 to +3 sites. Using this motif, novel SMYD2 peptide substrates were identified, leading to the discovery of 32 novel peptide substrates with a validated target site. Among them, 19 were previously reported to be methylated at the target lysine in human cells, strongly suggesting that SMYD2 is the protein lysine methyltransferase responsible for this activity. Methylation of some of the novel peptide substrates was tested at the protein level, leading to the identification of 14 novel protein substrates of SMYD2, six of which were more strongly methylated than p53, the best SMYD2 substrate described so far. The novel SMYD2 substrate proteins are involved in diverse biological processes such as chromatin regulation, transcription, and intracellular signaling. The results of our study provide a fundament for future investigations into the role of this important enzyme in normal development and cancer.

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The SUV39H1 Protein Lysine Methyltransferase Methylates Chromatin Proteins Involved in Heterochromatin Formation and VDJ Recombination

Cited by 31 publications

References 58 publications

Histone methyltransferase SUV 39H1 participates in host defense by methylating mycobacterial histone‐like protein HupB

Histone methyltransferase SUV 39H1 participates in host defense by methylating mycobacterial histone‐like protein HupB

The Oncogenic Potential of SUV39H2: A Comprehensive and Perspective View

Analysis of the Substrate Specificity of the SMYD2 Protein Lysine Methyltransferase and Discovery of Novel Non‐Histone Substrates

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