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KDM5B protein expressed in viable and fertile ΔARID mice exhibit no demethylase activity.
- Source :
-
International journal of oncology [Int J Oncol] 2021 Nov; Vol. 59 (5). Date of Electronic Publication: 2021 Oct 29. - Publication Year :
- 2021
-
Abstract
- Post‑translational 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 small‑molecular weight inhibitors of its demethylase activity have been identified. Previous characterisation of Kdm5b knock‑out mice has revealed that this genotype leads to either embryonic or neonatal lethality. However, the ΔA‑T 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, ΔARID‑KDM5B was found to have no demethylase activity as determined by in vitro demethylase assays and by immunofluorescence in transfected Cos‑1 cells. Furthermore, molecular dynamic simulations revealed conformational changes within the ΔARID‑KDM5B structure compared with that in WT‑KDM5B, particularly in the JmjC domain, which is responsible for the catalytic activity of WT‑KDM5B. This supports the experimental data that shows the loss of demethylase activity. Since Kdm5b knock‑out 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.
- Subjects :
- Animals
DNA Demethylation
DNA-Binding Proteins genetics
DNA-Binding Proteins ultrastructure
Enzyme Assays
Female
Fertility genetics
Gene Expression Regulation, Developmental
Jumonji Domain-Containing Histone Demethylases genetics
Jumonji Domain-Containing Histone Demethylases ultrastructure
Male
Mice
Mice, Transgenic
Molecular Dynamics Simulation
Protein Processing, Post-Translational genetics
DNA-Binding Proteins metabolism
Epigenesis, Genetic
Jumonji Domain-Containing Histone Demethylases metabolism
Protein Domains genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1791-2423
- Volume :
- 59
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- International journal of oncology
- Publication Type :
- Academic Journal
- Accession number :
- 34713299
- Full Text :
- https://doi.org/10.3892/ijo.2021.5276