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首页> 外文期刊>Cell Reports >SUMOylated ORC2 Recruits a Histone Demethylase to Regulate Centromeric Histone Modification and Genomic Stability
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SUMOylated ORC2 Recruits a Histone Demethylase to Regulate Centromeric Histone Modification and Genomic Stability

机译：SUMOylated ORC2招募组蛋白去甲基化酶来调节着丝粒组蛋白修饰和基因组稳定性

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摘要

Origin recognition complex 2 (ORC2), a subunit of the ORC, is essential for DNA replication initiation in eukaryotic cells. In addition to a role in DNA replication initiation at the G1/S phase, ORC2 has been shown to localize to the centromere during the G2/M phase. Here, we show that ORC2 is modified by small ubiquitin-like modifier 2 (SUMO2), but not SUMO1, at the G2/M phase of the cell cycle. SUMO2-modification of ORC2 is important for the recruitment of KDM5A in order to convert H3K4me3 to H3K4me2, a ''permissive'' histone marker for @a-satellite transcription at the centromere. Persistent expression of SUMO-less ORC2 led to reduced @a-satellite transcription and impaired pericentric heterochromatin silencing, which resulted in re-replication of heterochromatin DNA. DNA re-replication eventually activated the DNA damage response, causing the bypass of mitosis and the formation of polyploid cells. Thus, ORC2 sustains genomic stability by recruiting KDM5A to maintain centromere histone methylation in order to prevent DNA re-replication.
机译：起源识别复合物2（ORC2）是ORC的一个亚基，对于真核细胞中DNA复制的启动至关重要。除了在G1 / S期的DNA复制起始中发挥作用外，还显示ORC2在G2 / M期定位于着丝粒。在这里，我们显示在细胞周期的G2 / M期，ORC2被小的泛素样修饰剂2（SUMO2）修饰，而未被SUMO1修饰。为了将H3K4me3转化为H3K4me2，H3K4me3转化为着丝粒@a卫星转录的“允许”组蛋白标记，ORC2的SUMO2修饰对于募集KDM5A很重要。 SUMO-less ORC2的持续表达导致@a卫星转录降低和周向异染色质沉默受损，从而导致异染色质DNA的重复复制。 DNA复制最终激活了DNA损伤反应，导致有丝分裂的旁路和多倍体细胞的形成。因此，ORC2通过募集KDM5A来维持着丝粒组蛋白甲基化来维持基因组稳定性，从而防止DNA复制。

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