Taking Me away: the function of phosphorylation on histone lysine demethylases

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 49; no. 3; pp. 257 - 276
• Main Authors: Karakatsanis, Nicola M., Hamey, Joshua J., Wilkins, Marc R.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2024
• Subjects: chromatin accessibility; gene regulation; intrinsically disordered regions; lysine demethylase; protein–protein interaction; subcellular localization; lysine demethylase; protein–protein interaction; subcellular localization; gene regulation; chromatin accessibility; intrinsically disordered regions
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2023.12.004

Human histone demethylases are extensively phosphorylated, which can influence when and where they act on chromatin.Phosphorylation influences the function of histone demethylases via distinct mechanisms.Phosphorylation of histone demethylases occurs primarily in intrinsically disordered regions and at the interface of histone demethylase protein–protein interactions.Functional phospho-sites located in structural domains influence function through either domain-specific or domain-independent mechanisms. Histone lysine demethylases (KDMs) regulate eukaryotic gene transcription by catalysing the removal of methyl groups from histone proteins. These enzymes are intricately regulated by the kinase signalling system in response to internal and external stimuli. Here, we review the mechanisms by which kinase-mediated phosphorylation influence human histone KDM function. These include the changing of histone KDM subcellular localisation or chromatin binding, the altering of protein half-life, changes to histone KDM complex formation that result in histone demethylation, non-histone demethylation or demethylase-independent effects, and effects on histone KDM complex dissociation. We also explore the structural context of phospho-sites on histone KDMs and evaluate how this relates to function. Histone lysine demethylases (KDMs) regulate eukaryotic gene transcription by catalysing the removal of methyl groups from histone proteins. These enzymes are intricately regulated by the kinase signalling system in response to internal and external stimuli. Here, we review the mechanisms by which kinase-mediated phosphorylation influence human histone KDM function. These include the changing of histone KDM subcellular localisation or chromatin binding, the altering of protein half-life, changes to histone KDM complex formation that result in histone demethylation, non-histone demethylation or demethylase-independent effects, and effects on histone KDM complex dissociation. We also explore the structural context of phospho-sites on histone KDMs and evaluate how this relates to function.