Specificity of the SUV4–20H1 and SUV4–20H2 protein lysine methyltransferases and methylation of novel substrates

Weirich, Sara; Kudithipudi, Srikanth; Jeltsch, Albert

doi:10.1016/j.jmb.2016.04.015

Cited by 29 publications

(30 citation statements)

References 38 publications

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“…KMT5A. Prior to H4K20 di-or trimethylation, H4K20 must first be monomethylated (38)(39)(40). The enzyme responsible for H4K20 monomethylation is KMT5A (Aliases: SET8, SETD8, PR-SET7) (lysine methyltransferase 5A), a SET-domain (Su(var)3-9, Enhancer-of-zeste and Trithorax) containing methyltransferase (Table 1).…”

Section: H4k20me2mentioning

confidence: 99%

Understanding the Histone DNA Repair Code: H4K20me2 Makes Its Mark

Paquin

Howlett

2018

Molecular Cancer Research

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Chromatin is a highly compact structure that must be rapidly rearranged in order for DNA repair proteins to access sites of damage and facilitate timely and efficient repair. Chromatin plasticity is achieved through multiple processes, including the posttranslational modification of histone tails. In recent years, the impact of histone posttranslational modification on the DNA damage response has become increasingly well recognized, and chromatin plasticity has been firmly linked to efficient DNA repair. One particularly important histone posttranslational modification process is methylation. Here, we focus on the regulation and function of H4K20 methylation (H4K20me) in the DNA damage response and describe the writers, erasers, and readers of this important chromatin mark as well as the combinatorial histone posttranslational modifications that modulate H4K20me recognition. Finally, we discuss the central role of H4K20me in determining if DNA double-strand breaks (DSB) are repaired by the error-prone, nonhomologous DNA end joining pathway or the error-free, homologous recombination pathway. This review article discusses the regulation and function of H4K20me2 in DNA DSB repair and outlines the components and modifications that modulate this important chromatin mark and its fundamental impact on DSB repair pathway choice. .

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Section: H4k20me2mentioning

confidence: 99%

Understanding the Histone DNA Repair Code: H4K20me2 Makes Its Mark

Paquin

Howlett

2018

Molecular Cancer Research

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“…Our data suggest that an epigenetic factor and bona fide tumor suppressor, SUV420H2 can be included among the gatekeepers of the genome. SUV420H2 catalyzes the trimethylation of histone H4 at lysine-20 (H4K20) using mono-methylated H4K20 as a substrate, which is required for the establishment of heterochromatin and repression of genes (Hahn et al, 2013;Schotta et al, 2008;Weirich et al, 2016). Loss of SUV420H2 has previously been implicated in causation of multiple cancers (Fraga et al, 2005;Pogribny et al, 2007), but for the first time we show that loss of SUV420H2 is a novel mechanism that promotes erlotinib resistance in NSCLC cells.…”

Section: Introductionmentioning

confidence: 68%

Loss of SUV420H2 promotes EGFR inhibitor resistance in NSCLC through upregulation of MET via LINC01510

Pal

Agredo

Lanman

et al. 2020

Preprint

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Epidermal growth factor receptor inhibitors (EGFRi) are standard-of-care treatments administered to patients with non-small cell lung cancer (NSCLC) that harbor EGFR alterations.However, development of resistance within a year post-treatment remains a major challenge.Multiple mechanisms can promote survival of EGFRi treated NSCLC cells, including secondary mutations in EGFR and activation of bypass tracks that circumvent the requirement for EGFR signaling. Nevertheless, mechanisms involved in bypass track activation are understudied, and in a subset of cases the mechanisms are unknown. The findings from this study identified an epigenetic factor, SUV420H2 that when lost drives resistance of NSCLC to multiple EGFRi, including erlotinib, gefitinib, afatinib, and osimertinib. SUV420H2 catalyzes trimethylation of histone H4 lysine-20, a modification required for gene repression and maintenance of heterochromatin. Here we show that loss of SUV420H2 leads to upregulation of an oncogenic long non-coding RNA, LINC01510 that promotes transcription of the oncogene MET, a component of a major bypass track involved in EGFRi resistance. Significance:Due to an incomplete understanding of the mechanisms involved in promoting resistance to EGFRi, patients often succumb to their disease. Here we identified a global mediator of EGFRi resistance, SUV420H2 that helps to uncover an additional mechanism involved in resistance driven via a major bypass track involving the protooncogene MET. Supplementary information can be found online at Acknowledgments:The authors gratefully acknowledge the support of multiple core facilities from the Purdue

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“…Better understanding of the biology of the SMYD2 protein lysine methylation signaling network critically depends on the identification of the substrate profile of SMYD2, but in spite of progress in this direction, the identification of PKMT substrates is not trivial . General proteome‐wide screenings were undertaken aiming to identify SMYD2 substrates in an unbiased way.…”

Section: Introductionmentioning

confidence: 99%

“…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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Specificity of the SUV4–20H1 and SUV4–20H2 protein lysine methyltransferases and methylation of novel substrates

Cited by 29 publications

References 38 publications

Understanding the Histone DNA Repair Code: H4K20me2 Makes Its Mark

Understanding the Histone DNA Repair Code: H4K20me2 Makes Its Mark

Loss of SUV420H2 promotes EGFR inhibitor resistance in NSCLC through upregulation of MET via LINC01510

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

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