CRL4(Cdt2) 介导的组蛋白甲基转移酶 Set8 的降解可防止 S 期过早发生染色质浓缩。
CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase.
机构信息
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
出版信息
Mol Cell. 2010 Oct 8;40(1):22-33. doi: 10.1016/j.molcel.2010.09.015.
The proper coordination between DNA replication and mitosis during cell-cycle progression is crucial for genomic stability. During G2 and mitosis, Set8 catalyzes monomethylation of histone H4 on lysine 20 (H4K20me1), which promotes chromatin compaction. Set8 levels decline in S phase, but why and how this occurs is unclear. Here, we show that Set8 is targeted for proteolysis in S phase and in response to DNA damage by the E3 ubiquitin ligase, CRL4(Cdt2). Set8 ubiquitylation occurs on chromatin and is coupled to DNA replication via a specific degron in Set8 that binds PCNA. Inactivation of CRL4(Cdt2) leads to Set8 stabilization and aberrant H4K20me1 accumulation in replicating cells. Transient S phase expression of a Set8 mutant lacking the degron promotes premature H4K20me1 accumulation and chromatin compaction, and triggers a checkpoint-mediated G2 arrest. Thus, CRL4(Cdt2)-dependent destruction of Set8 in S phase preserves genome stability by preventing aberrant chromatin compaction during DNA synthesis.
在细胞周期进程中，DNA 复制和有丝分裂之间的适当协调对于基因组稳定性至关重要。在 G2 和有丝分裂期间，Set8 催化组蛋白 H4 赖氨酸 20 上的单甲基化（H4K20me1），促进染色质紧缩。Set8 水平在 S 期下降，但为什么会发生这种情况以及如何发生仍不清楚。在这里，我们表明 Set8 在 S 期和响应 DNA 损伤时通过 E3 泛素连接酶 CRL4（Cdt2）被靶向进行蛋白水解。Set8 的泛素化发生在染色质上，并通过 Set8 上与 PCNA 结合的特定降解基序与 DNA 复制偶联。CRL4（Cdt2）的失活导致 Set8 稳定，并在复制细胞中导致异常的 H4K20me1 积累。瞬时 S 期表达缺乏降解基序的 Set8 突变体可促进过早的 H4K20me1 积累和染色质紧缩，并引发检查点介导的 G2 期阻滞。因此，CRL4（Cdt2）依赖性 S 期 Set8 降解通过防止 DNA 合成过程中异常染色质紧缩来维持基因组稳定性。
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