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Mol Biotechnol ; 63(1): 53-62, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33130996

RESUMO

The repressor element 1 (RE1) silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) modulates the expression of genes with RE1/neuron-restrictive silencing element (RE1/NRSE) sites by recruiting the switch independent 3 (SIN3) factor and the REST corepressor (COREST) to its N and C-terminal repressor domain, respectively. Both, SIN3 and COREST assemble into protein complexes that are composed of multiple subunits including a druggable histone deacetylase (HDAC) enzyme. The SIN3 core complex comprises the eponymous proteins SIN3A or SIN3B, the catalytically active proteins HDAC1 or HDAC2, the histone chaperone retinoblastoma-associated protein 46/retinoblastoma-binding protein 7 (RBAP46/RBBP7) or RBAP48/RBBP4, the SIN3-associated protein 30 (SAP30), and the suppressor of defective silencing 3 (SDS3). Here, we overcome a bottleneck limiting the molecular characterization of the REST/NRSF-SIN3 transcriptional corepressor complex. To this end, SIN3 genes were amplified from the complementary DNA of neural stem/progenitor cells, and expressed in a baculovirus/insect cell expression system. We show that the isolates bind to DNA harboring RE1/NRSE sites and demonstrate that the histone deacetylase activity is blocked by small-molecule inhibitors. Thus, our isolates open up for future biomedical research on this critical transcriptional repressor complex and are envisioned as tool for drug testing.


Assuntos
Proteínas Correpressoras/genética , Inibidores de Histona Desacetilases/farmacologia , Proteínas do Tecido Nervoso/genética , Células-Tronco Neurais/metabolismo , Proteínas Repressoras/genética , Complexo Correpressor Histona Desacetilase e Sin3/genética , Complexo Correpressor Histona Desacetilase e Sin3/isolamento & purificação , Animais , Baculoviridae/metabolismo , Benzamidas/farmacologia , Proteínas Correpressoras/isolamento & purificação , Proteínas Correpressoras/metabolismo , Depsipeptídeos/farmacologia , Biblioteca Gênica , Histona Desacetilases/metabolismo , Humanos , Proteínas do Tecido Nervoso/isolamento & purificação , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/enzimologia , Pirimidinas/farmacologia , Proteínas Recombinantes , Elementos Reguladores de Transcrição/genética , Proteínas Repressoras/isolamento & purificação , Proteínas Repressoras/metabolismo , Células Sf9 , Complexo Correpressor Histona Desacetilase e Sin3/metabolismo
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