KDM4C (GASC1) lysine demethylase is associated with mitotic chromatin and regulates chromosome segregation during mitosis

Abstract

Various types of human cancers exhibit amplification or deletion of KDM4A-D members, which selectively demethylate H3K9 and H3K36, thus implicating their activity in promoting carcinogenesis. On this basis, it was hypothesized that dysregulated expression of KDM4A-D family promotes chromosomal instabilities by largely unknown mechanisms. Here, we show that unlike KDM4A-B, KDM4C is associated with chromatin during mitosis. This association is accompanied by a decrease in the mitotic levels of H3K9me3. We also show that the C-terminal region, containing the Tudor domains of KDM4C, is essential for its association with mitotic chromatin. More specifically, we show that R919 residue on the proximal Tudor domain of KDM4C is critical for its association with chromatin during mitosis. Interestingly, we demonstrate that depletion or overexpression of KDM4C, but not KDM4B, leads to over 3-fold increase in the frequency of abnormal mitotic cells showing either misaligned chromosomes at metaphase, anaphase–telophase lagging chromosomes or anaphase–telophase bridges. Furthermore, overexpression of KDM4C demethylase-dead mutant has no detectable effect on mitotic chromosome segregation. Altogether, our findings implicate KDM4C demethylase activity in regulating the fidelity of mitotic chromosome segregation by a yet unknown mechanism.

Reader domain specificity and lysine demethylase-4 family function

“…8), suggesting functional diversification as a result of genome duplication during evolution. The sophisticated intermolecular interactions present in KDM4-DTDs revealed by this study underlies the histone interactomes of human KDM4A–C DTDs and sheds light on distinct functions of KDM4 members141516. The mild phenotype of individual KDM4 knockout mice4041 implicates some compensating functions among KDM4 members, which is consistent with overlapping histone PTM interactomes among KDM4A–C DTDs (Fig.…”

“…The amino-terminal catalytic domains of KDM4A–C display demethylase activity that can convert di-/trimethylated lysines to lower methylated states at H3K9 and H3K36 with comparable kinetics13. Despite similar catalytic activities, individual KDM4 members exhibit varied chromatin associations and biological functions141516. These observations suggest an uncharacterized mechanism controls KDM4 protein functions on chromatin.…”

“…In particular, DTD from KDM4A (KDM4A-DTD) was shown to form an unique integral structural unit and recognize methylated lysines222324252627. Deletion of the C-terminal domain in KDM4 proteins resulted in a change of sub-cellular localization, changed demethylase activity and disruption of other KDM4 functions8141528, suggesting functional roles for the C-terminal DTDs. However, there has been no comprehensive investigation of the histone-binding properties for KDM4B and KDM4C DTDs.…”

Drosophila Histone Demethylase KDM4A Has Enzymatic and Non-enzymatic Roles in Controlling Heterochromatin Integrity

“…Members of this family play vital roles in epigenetic mechanisms that govern gene expression and development (Nottke, Colaiacovo et al 2009, Lorbeck, Singh et al 2010), regulate DNA repair and genome stability (Mallette, Mattiroli et al 2012, Kupershmit, Khoury-Haddad et al 2014, Awwad and Ayoub 2015), and are misregulated in many types of cancers (Black, Manning et al 2013, Guerra-Calderas, Gonzalez-Barrios et al 2015). Despite its name, the closest dKDM4A mammalian homolog is KDM4D, since both contain the JmjN and JmjC domains responsible for enzymatic activity, and lack the PHD and Tudor domains found in human KDM4A (Lloret-Llinares, Carré et al 2008).…”

The emerging role of lysine demethylases in DNA damage response: dissecting the recruitment mode of KDM4D/JMJD2D to DNA damage sites

“…These results highlight a causative role of KDM4C lysine demethylase in regulating the fidelity of mitotic chromosome segregation. 99 Furthermore, it was shown that KDM2A depletion promotes genomic instability as evident by the destabilization of centromeric chromatin during mitosis 100 and the increase in the percentage of cells showing micronuclei or chromosome bridges. 101 Finally, an important study showed that overexpression of a catalytically active KDM4A protein induces copy number gains of specific genomic regions, which are known to contain oncogenes.…”