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Review
. 2024 Jun 24;25(13):6900.
doi: 10.3390/ijms25136900.

To Erase or Not to Erase: Non-Canonical Catalytic Functions and Non-Catalytic Functions of Members of Histone Lysine Demethylase Families

Elena Di Nisio  1 , Valeria Manzini  1   2 , Valerio Licursi  2 , Rodolfo Negri  1   2
Affiliations
Review

To Erase or Not to Erase: Non-Canonical Catalytic Functions and Non-Catalytic Functions of Members of Histone Lysine Demethylase Families

Elena Di Nisio et al. Int J Mol Sci. .

Abstract

Histone lysine demethylases (KDMs) play an essential role in biological processes such as transcription regulation, RNA maturation, transposable element control, and genome damage sensing and repair. In most cases, their action requires catalytic activities, but non-catalytic functions have also been shown in some KDMs. Indeed, some strictly KDM-related proteins and some KDM isoforms do not act as histone demethylase but show other enzymatic activities or relevant non-enzymatic functions in different cell types. Moreover, many studies have reported on functions potentially supported by catalytically dead mutant KDMs. This is probably due to the versatility of the catalytical core, which can adapt to assume different molecular functions, and to the complex multi-domain structure of these proteins which encompasses functional modules for targeting histone modifications, promoting protein-protein interactions, or recognizing nucleic acid structural motifs. This rich modularity and the availability of multiple isoforms in the various classes produced variants with enzymatic functions aside from histone demethylation or variants with non-catalytical functions during the evolution. In this review we will catalog the proteins with null or questionable demethylase activity and predicted or validated inactive isoforms, summarizing what is known about their alternative functions. We will then go through some experimental evidence for the non-catalytical functions of active KDMs.

Keywords: cancer epigenetics; catalytic-independent functions; histone demethylases; histone modifications; protein isoforms.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic representation of the predicted and validated transcripts for KDM4 and KDM5 genes (from NCBI Gene RefSeq database). Each of these transcripts could generate different predicted or validated protein isoforms with or without known protein domains, resulting in non-truncated or truncated isoforms. Among the truncated protein isoforms, we highlighted the absence of JmjN, JmjC, or both of these domains, using orange, purple, and blue, respectively. Green arrows show the translational start sites for transcripts giving rise to shorter protein isoforms. For KDM4A, KDM4D, KDM5A, KDM5C, and KDM5D, no truncated protein isoforms were predicted. More details are in Table S1. Figure 1 was created using R v4.3.1 and ggplot2 package v3.5.1. Final editing with Inkscape 1.3.2.
Figure 2
Figure 2
Model of the competitive action of the KDM5B-NTT isoform on the KDM5B-PLU1 targets. Created with BioRender.com.
Figure 3
Figure 3
Schematic representation of different protein domains that confer demethylase activity or determine demethylase-independent functions, including other enzymatic activities, which in turn regulate many biological processes. Created with Biorender.com.
See this image and copyright information in PMC

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