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The KDM5B protein expressed in the viable and fertile ΔARID mouse has no demethylase activity

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
JournalInternational Journal of Oncology
Accepted/In press5 Aug 2021

King's Authors

Abstract

Post-translational modifications of histones play a crucial role in the control of gene transcription. Trimethylation of lysine 4 in histone 3 is associated with active transcription and there are six methylases and six demethylases that control methylation of this site. KDM5B is one such demethylase which can repress gene expression. Importantly, KDM5B is over-expressed in a number of cancer types and small molecular weight inhibitors of its demethylase activity have been identified. The characterisation of Kdm5b knock-out mice has shown Kdm5b knock-out leads to embryonic lethality or neonatal lethality. However, the ARID strain of mice which have the ARID domain and five amino acids of the JmjN domain spliced out are viable and fertile. Here we show that KDM5B with the deletion observed in the ARID mice (ARID-KDM5B), has no demethylase activity as determined in vitro and in cell lines. Furthermore, molecular dynamic simulations show conformational changes in ARID-KDM5B compared to WT-KDM5B, particularly in the catalytic JmjC region. This supports the experimental data that shows loss of demethylase activity. As the Kdm5b knock-out mice show degrees of lethality, these data strongly indicate that KDM5B has a crucial function in development that is independent of its demethylase activity.

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