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1.
Mol Biol Cell ; 34(1): ar6, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36416860

RESUMO

Set1 is an H3K4 methyltransferase that comprises the catalytic subunit of the COMPASS complex and has been implicated in transcription, DNA repair, cell cycle control, and numerous other genomic functions. Set1 also promotes proper telomere maintenance, as cells lacking Set1 have short telomeres and disrupted subtelomeric gene repression; however, the precise role for Set1 in these processes has not been fully defined. In this study, we have tested mutants of Set1 and the COMPASS complex that differentially alter H3K4 methylation status, and we have attempted to separate catalytic and noncatalytic functions of Set1. Our data reveal that Set1-dependent subtelomeric gene repression relies on its catalytic activity toward H3K4, whereas telomere length is regulated by Set1 catalytic activity but likely independent of the H3K4 substrate. Furthermore, we uncover a role for Set1 in calibrating the abundance of critical telomere maintenance proteins, including components of the telomerase holoenzyme and members of the telomere capping CST (Cdc13-Stn1-Ten1) complex, through both transcriptional and posttranscriptional pathways. Altogether, our data provide new insights into the H3K4 methylation-dependent and -independent roles for Set1 in telomere maintenance in yeast and shed light on possible roles for Set1-related methyltransferases in other systems.


Assuntos
Proteínas de Saccharomyces cerevisiae , Metilação , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Telômero/metabolismo , Proteínas de Ligação a Telômeros/metabolismo
2.
Sci Adv ; 9(46): eadi5921, 2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37976356

RESUMO

Aberrant activation of Ras/Raf/mitogen-activated protein kinase (MAPK) signaling is frequently linked to metastatic prostate cancer (PCa); therefore, the characterization of modulators of this pathway is critical for defining therapeutic vulnerabilities for metastatic PCa. The lysine methyltransferase SET and MYND domain 3 (SMYD3) methylates MAPK kinase kinase 2 (MAP3K2) in some cancers, causing enhanced activation of MAPK signaling. In PCa, SMYD3 is frequently overexpressed and associated with disease severity; however, its molecular function in promoting tumorigenesis has not been defined. We demonstrate that SMYD3 critically regulates tumor-associated phenotypes via its methyltransferase activity in PCa cells and mouse xenograft models. SMYD3-dependent methylation of MAP3K2 promotes epithelial-mesenchymal transition associated behaviors by altering the abundance of the intermediate filament vimentin. Furthermore, activation of the SMYD3-MAP3K2 signaling axis supports a positive feedback loop continually promoting high levels of SMYD3. Our data provide insight into signaling pathways involved in metastatic PCa and enhance understanding of mechanistic functions for SMYD3 to reveal potential therapeutic opportunities for PCa.


Assuntos
Neoplasias da Próstata , Masculino , Camundongos , Animais , Humanos , Neoplasias da Próstata/genética , Transdução de Sinais , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Metiltransferases/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , MAP Quinase Quinase Quinase 2/genética , MAP Quinase Quinase Quinase 2/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo
3.
Commun Biol ; 4(1): 147, 2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514864

RESUMO

Primary neurulation is the process by which the neural tube, the central nervous system precursor, is formed from the neural plate. Incomplete neural tube closure occurs frequently, yet underlying causes remain poorly understood. Developmental studies in amniotes and amphibians have identified hingepoint and neural fold formation as key morphogenetic events and hallmarks of primary neurulation, the disruption of which causes neural tube defects. In contrast, the mode of neurulation in teleosts has remained highly debated. Teleosts are thought to have evolved a unique mode of neurulation, whereby the neural plate infolds in absence of hingepoints and neural folds, at least in the hindbrain/trunk where it has been studied. Using high-resolution imaging and time-lapse microscopy, we show here the presence of these morphological landmarks in the zebrafish anterior neural plate. These results reveal similarities between neurulation in teleosts and other vertebrates and hence the suitability of zebrafish to understand human neurulation.


Assuntos
Células Epiteliais/fisiologia , Placa Neural/embriologia , Tubo Neural/embriologia , Neurulação , Prosencéfalo/embriologia , Peixe-Zebra/embriologia , Animais , Animais Geneticamente Modificados , Movimento Celular , Forma Celular , Células Epiteliais/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Morfogênese , Placa Neural/metabolismo , Tubo Neural/metabolismo , Defeitos do Tubo Neural/embriologia , Prosencéfalo/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Fatores de Tempo , Imagem com Lapso de Tempo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
4.
Life Sci Alliance ; 4(12)2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34625508

RESUMO

The yeast chromatin protein Set4 is a member of the Set3-subfamily of SET domain proteins which play critical roles in the regulation of gene expression in diverse developmental and environmental contexts. We previously reported that Set4 promotes survival during oxidative stress and regulates expression of stress response genes via stress-dependent chromatin localization. In this study, global gene expression analysis and investigation of histone modification status identified a role for Set4 in maintaining gene repressive mechanisms within yeast subtelomeres under both normal and stress conditions. We show that Set4 works in a partially overlapping pathway to the SIR complex and the histone deacetylase Rpd3 to maintain proper levels of histone acetylation and expression of stress response genes encoded in subtelomeres. This role for Set4 is particularly critical for cells under hypoxic conditions, where the loss of Set4 decreases cell fitness and cell wall integrity. These findings uncover a new regulator of subtelomeric chromatin that is key to stress defense pathways and demonstrate a function for Set4 in regulating repressive, heterochromatin-like environments.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Regulação Fúngica da Expressão Gênica , Histona Desacetilases/metabolismo , Estresse Oxidativo/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/genética , Telômero/metabolismo , Acetilação , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/genética , Inativação Gênica , Código das Histonas/genética , Histonas/metabolismo , Microrganismos Geneticamente Modificados/genética , Proteínas de Saccharomyces cerevisiae/genética , Transdução de Sinais/genética , Telômero/genética
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