Journal
INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 59, Issue 5, Pages -Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2021.5276
Keywords
histone demethylases; lysine demethylase 5B; Delta A-T rich interaction domain mice; loss of demethylase activity; molecular dynamics simulation
Categories
Funding
- CRUK KHP Centre Grant [C604/A25135]
- Blood Cancer UK [20002]
- Biotechnology and Biological Sciences Research [BB/T007737/1]
- Medical Research Council [MR/T015845/1]
- King's College London
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Post-translational modification of histones plays a crucial role in gene transcription control, with KDM5B being an overexpressed demethylase in various cancers. The study showed that Delta ARID-KDM5B, lacking demethylase activity, can still survive and reproduce in mice, suggesting a crucial role of KDM5B in development independent of its demethylase activity.
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 AA-T rich interaction domain (Delta ARID)-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, Delta ARID-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 Delta ARID-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.
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