Abstract
The KDM4 family of lysine demethylases consists of five members, KDM4A, -B and -C that demethylate H3K9me2/3 and H3K36me2/3 marks, while KDM4D and -E demethylate only H3K9me2/3. Recent studies implicated KDM4 proteins in regulating genomic instability and carcinogenesis. Here, we describe a previously unrecognized pathway by which hyperactivity of KDM4 demethylases promotes genomic instability. We show that overexpression of KDM4A-C, but not KDM4D, disrupts MSH6 foci formation during S phase by demethylating its binding site, H3K36me3. Consequently, we demonstrate that cells overexpressing KDM4 members are defective in DNA mismatch repair (MMR), as evident by the instability of four microsatellite markers and the remarkable increase in the spontaneous mutations frequency at the HPRT locus. Furthermore, we show that the defective MMR in cells overexpressing KDM4C is mainly due to the increase in its demethylase activity and can be mended by KDM4C downregulation. Altogether, our data suggest that cells overexpressing KDM4A-C are defective in DNA MMR and this may contribute to genomic instability and tumorigenesis.
Highlights
A decade ago, two families of lysine demethylases (KDM) have been identified, confirming that lysine methylation is a reversible and dynamically regulated process (Klose et al, 2006a; Shi et al, 2004; Whetstine et al, 2006)
Our data suggest that cells overexpressing KDM4A-C are defective in DNA mismatch repair (MMR) and this may contribute to genomic instability and tumorigenesis
We show that overexpression of KDM4 impairs the integrity of DNA mismatch repair (MMR) and leading to microsatellite instability (MSI) and to an increase in the frequency of spontaneous mutations
Summary
A decade ago, two families of lysine demethylases (KDM) have been identified, confirming that lysine methylation is a reversible and dynamically regulated process (Klose et al, 2006a; Shi et al, 2004; Whetstine et al, 2006). We demonstrate that cells overexpressing KDM4 members are defective in DNA mismatch repair (MMR), as evident by the instability of four microsatellite markers and the remarkable increase in the spontaneous mutations frequency at the HPRT locus. We show that overexpression of KDM4 impairs the integrity of DNA mismatch repair (MMR) and leading to microsatellite instability (MSI) and to an increase in the frequency of spontaneous mutations.
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