The Smyd family of methyltransferases: role in cardiac and skeletal muscle physiology and pathology

Tracy, Christopher M.; Warren, Jason G.; Szulik, Marta W.; Wang, Li; Garcia, June; Makaju, Aman; Russell, Kristi; Miller, Matt; Franklin, Sarah

doi:10.1016/j.cophys.2017.10.001

Cited by 83 publications

(127 citation statements)

References 76 publications

(139 reference statements)

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“…This gene -not yet considered morbid -is highly expressed in the developing fetal heart. Of note, both Smyd3 knockout and knockdown models were related to different cardiac defects [Tracy et al, 2018]. (9), while subtelomeric 9q green signals are observed on the normal chromosome 9 and on the der(1).…”

Section: Discussionmentioning

confidence: 99%

Familial 3-Way Balanced Translocation Causes 1q43→qter Loss and 10q25.2→qter Gain in a Severely Affected Male Toddler

Córdova-Fletes

Arámbula-Meraz

Zarazúa-Niño

et al. 2019

Cytogenet Genome Res

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Constitutional complex chromosomal rearrangements (CCRs) are rare events that typically involve 2 or more chromosomes with at least 3 breakpoints and can result in normal or abnormal phenotypes depending on whether they disturb the euchromatic neighborhood. Here, we report an unusual balanced CCR involving chromosomes 1, 9, and 10 that causes an unbalanced karyotype in a severely affected toddler. The CCR was initially reported as a maternal 2-way translocation but was reclassified as a 3-way translocation after a microarray analysis of the propositus revealed the involvement of another chromosome not identified by G-banding in his phenotypically normal mother. FISH assays on maternal metaphase cells confirmed that the 1qter region of der(1) was translocated to der(10), whereas the 10qter segment was translocated to der(9), which in turn donated a segment to der(1). Subsequently, this CCR was also identified in her phenotypically normal father (the patient's grandfather). Thus, the patient inherited the previously unreported pathogenic combination of der(1) with a loss of 1q43→qter (including AKT3, ZBTB18, HNRNPU, and SMYD3) and der(9) with a gain of 10q25.2→qter (including FGFR2), leading to a compound phenotype with key features of the 1q43→qter deletion and distal 10q trisomy syndromes. Our observations suggest that the loss of SMYD3 accounts for cardiac defects in a subset of patients. Moreover, due to recurrent miscarriages in this family, our findings allowed improved genetic counseling.

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Section: Discussionmentioning

confidence: 99%

Familial 3-Way Balanced Translocation Causes 1q43→qter Loss and 10q25.2→qter Gain in a Severely Affected Male Toddler

Córdova-Fletes

Arámbula-Meraz

Zarazúa-Niño

et al. 2019

Cytogenet Genome Res

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“…Furthermore, in addition to core transcription components and chromatin remodelers we identified a series of chromatin modifying enzymes including SUV420H2, a histone H4K20 methyltransferase (Schotta et al, 2004), EZH2, the PRC2 complex component responsible for H3K27 methylation (Margueron and Reinberg, 2011), SETD2 the principle H3K36 methyl transferase (Edmunds et al, 2008;Yuan et al, 2009), EHMT2 (G9A) is a H3K9 specific methyltransferase (Krishnan et al, 2011) and SMYD1 an SET domain protein that potentially targets histones (Tracy et al, 2018). The variety of modifiers that impact on CENP-A maintenance suggests that a chromatin imbalance, whether it is activating or repressing for gene expression, has a deleterious effect on CENP-A chromatin maintenance.…”

Section: Common Themes Among Factors Involved In Cenp-a Maintenancementioning

confidence: 99%

Genetic screening identifies a SUMO protease dynamically maintaining centromeric chromatin and the associated centromere complex

Mitra

Bodor

David

et al. 2019

Preprint

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Centromeres are defined by a unique self-propagating chromatin structure featuring nucleosomes containing the histone H3 variant CENP-A. CENP-A turns over slower than general chromatin and a key question is whether this unusual stability is intrinsic to CENP-A nucleosomes or rather imposed by external factors. We designed a specific genetic screen to identify proteins involved in CENP-A stability based on SNAP-tag pulse chase labeling. Using a double pulse-labeling approach we simultaneously assay for factors with selective roles in CENP-A chromatin assembly. We discover a series of new proteins involved in CENP-A propagation, including proteins with known roles in DNA replication, repair and chromatin modification and transcription, revealing that a broad set of chromatin regulators impacts in CENP-A transmission through the cell cycle.The key factor we find to strongly affect CENP-A stability is SENP6. This SUMO-protease controls not only the levels of chromatin bound CENP-A but is required for the maintenance of virtually the entire centromere and kinetochore, with the exception of CENP-B. Acute depletion of SENP6 protein reveals its requirement for maintaining centromeric CENP-A levels throughout the cell cycle, suggesting that a dynamic SUMO cycle underlies a continuous surveillance of the centromere complex.

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“…Lysine residues can be mono‐, di‐ and trimethylated and the biological outcome of the modification depends on the site and degree of methylation in target proteins. Lysine methylation is introduced by protein lysine methyltransferases (PKMTs) including enzymes of the SET and MYND‐containing protein (SMYD) family . The biological function of SMYD PKMTs is diverse including gene regulation, chromatin remodeling, transcription, signal transduction, cell cycle control, and DNA damage response .…”

Section: Introductionmentioning

confidence: 99%

“…In addition, several other non‐histone targets were identified in the last couple of years, including PARP1, MAPKAPK3 and PTEN . SMYD2 is essential for normal organismal development and dysregulation of SMYD2 was found in cardiovascular disease and cancer . For example, SMYD2 is significantly overexpressed in many cancers including esophageal squamous cell carcinoma (ESCC), bladder and gastric cancer, and in triple negative breast cancer it was shown to have a tumor promoting effect .…”

Section: Introductionmentioning

confidence: 99%

“…SMYD2 is essential for normal organismal development and dysregulation of SMYD2 was found in cardiovascular disease and cancer . For example, SMYD2 is significantly overexpressed in many cancers including esophageal squamous cell carcinoma (ESCC), bladder and gastric cancer, and in triple negative breast cancer it was shown to have a tumor promoting effect . In some cases, the molecular mechanisms connecting the methylation of SMYD2 non‐histone substrates and oncogenic effects have been discovered and, based on these, inhibitors of SMYD2 have been tested as therapeutic agents …”

Section: Introductionmentioning

confidence: 99%

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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 Smyd family of methyltransferases: role in cardiac and skeletal muscle physiology and pathology

Cited by 83 publications

References 76 publications

Familial 3-Way Balanced Translocation Causes 1q43→qter Loss and 10q25.2→qter Gain in a Severely Affected Male Toddler

Familial 3-Way Balanced Translocation Causes 1q43→qter Loss and 10q25.2→qter Gain in a Severely Affected Male Toddler

Genetic screening identifies a SUMO protease dynamically maintaining centromeric chromatin and the associated centromere complex

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

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The Smyd family of methyltransferases: role in cardiac and skeletal muscle physiology and pathology

Cited by 83 publications

References 76 publications

Familial 3-Way Balanced Translocation Causes 1q43&#x2192;qter Loss and 10q25.2&#x2192;qter Gain in a Severely Affected Male Toddler

Familial 3-Way Balanced Translocation Causes 1q43&#x2192;qter Loss and 10q25.2&#x2192;qter Gain in a Severely Affected Male Toddler

Genetic screening identifies a SUMO protease dynamically maintaining centromeric chromatin and the associated centromere complex

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

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Familial 3-Way Balanced Translocation Causes 1q43→qter Loss and 10q25.2→qter Gain in a Severely Affected Male Toddler

Familial 3-Way Balanced Translocation Causes 1q43→qter Loss and 10q25.2→qter Gain in a Severely Affected Male Toddler