KDM5B protein expressed in viable and fertile ΔARID mice exhibit no demethylase activity.
Int J Oncol
; 59(5)2021 11.
Article
em En
| MEDLINE
| ID: mdl-34713299
ABSTRACT
Posttranslational modification of histones serve a crucial role in the control of gene transcription. Trimethylation of lysine 4 on histone 3 is associated with transcription activation. There are currently six known methylases and six known demethylases that can control the methylation status of this site. Lysine demethylase 5B (KDM5B) is one such demethylase, which can repress gene expression. In particular KDM5B has been found to be overexpressed in a number of cancer types, and smallmolecular weight inhibitors of its demethylase activity have been identified. Previous characterisation of Kdm5b knockout mice has revealed that this genotype leads to either embryonic or neonatal lethality. However, the ΔAT rich interaction domain (ΔARID)KDM5B strain of mice, which have the ARID domain and five amino acids within the Jumonji (Jmj)N domain spliced out from KDM5B, remain viable and fertile. In the present study, ΔARIDKDM5B was found to have no demethylase activity as determined by in vitro demethylase assays and by immunofluorescence in transfected Cos1 cells. Furthermore, molecular dynamic simulations revealed conformational changes within the ΔARIDKDM5B structure compared with that in WTKDM5B, particularly in the JmjC domain, which is responsible for the catalytic activity of WTKDM5B. This supports the experimental data that shows the loss of demethylase activity. Since Kdm5b knockout mice show varying degrees of lethality, these data suggest that KDM5B serves a crucial function in development in a manner that is independent of its demethylase activity.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Epigênese Genética
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Proteínas de Ligação a DNA
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Histona Desmetilases com o Domínio Jumonji
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Domínios Proteicos
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article