Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway.
Overexpression of KDM4 lysine demethylases disrupts the integrity of the DNA mismatch repair pathway.
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DOI：
10.1242/bio.201410991
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发表时间：
2015-03-13
期刊：
影响因子：
2.4
通讯作者：
Ayoub N
中科院分区：
文献类型：
--
作者：
Awwad SW;Ayoub N
赖氨酸脱甲基酶的KDM 4家族由五个成员组成，KDM 4A、-B和-C，其使H3 K9 me 2/3和H3 K36 me 2/3标记脱甲基，而KDM 4D和-E仅使H3 K9 me 2/3脱甲基。最近的研究表明，KDM 4蛋白在调节基因组不稳定性和致癌作用。在这里，我们描述了一个以前未被认识的途径，其中KDM 4脱甲基酶的过度活跃促进基因组的不稳定性。我们发现，KDM 4A-C的过表达，而不是KDM 4D，破坏MSH 6病灶形成在S期通过去甲基化其结合位点，H3 K36 me 3。因此，我们证明，细胞过表达KDM 4成员是有缺陷的DNA错配修复（MMR），明显的不稳定性的四个微卫星标记和显着增加的自发突变频率在HPRT基因座。此外，我们表明，在细胞中过表达KDM 4C的缺陷MMR主要是由于其脱甲基酶活性的增加，可以通过KDM 4C下调修复。总而言之，我们的数据表明，过表达KDM 4A-C的细胞在DNA MMR方面存在缺陷，这可能导致基因组不稳定和肿瘤发生。
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.
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