Rad54B serves as a scaffold in the DNA damage response that limits checkpoint strength
Rad54B serves as a scaffold in the DNA damage response that limits checkpoint strength
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DOI：
10.1038/ncomms6426
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发表时间：
2014-11-01
影响因子：
16.6
通讯作者：
Miyagawa, Kiyoshi
中科院分区：
文献类型：
--
作者：
Yasuhara, Takaaki;Suzuki, Takahiko;Miyagawa, Kiyoshi
DNA 损伤检查点的强度对细胞命运至关重要，但 DNA 损伤反应 (DDR) 期间检查点强度微调背后的机制尚不清楚。在这里，我们证明 Rad54B（一种 SNF2 解旋酶样 DNA 修复蛋白）限制 G1/S 和 G2/M 检查点的强度。我们发现 Rad54B 通过与 MDM2-MDMX 泛素连接酶复合物直接相互作用而充当 p53 降解的支架。在 DDR 的早期阶段，Rad54B 上调，从而维持低检查点强度并促进细胞周期进展。一旦 p53 介导的检查点建立，Rad54B 就会下调，并保持高检查点强度。在肿瘤中经常观察到 Rad54B 活性的组成性上调，由于检查点覆盖而促进基因组不稳定。因此，Rad54B 的支架功能通过限制检查点强度来动态调节基因组完整性的维持。
The strength of the DNA damage checkpoint critically influences cell fate, yet the mechanisms behind the fine tuning of checkpoint strength during the DNA damage response (DDR) are poorly understood. Here we show that Rad54B-a SNF2 helicase-like DNA-repair protein-limits the strength of both the G1/S and G2/M checkpoints. We find that Rad54B functions as a scaffold for p53 degradation via its direct interaction with the MDM2-MDMX ubiquitin-ligase complex. During the early phases of the DDR, Rad54B is upregulated, thereby maintaining low checkpoint strength and facilitating cell cycle progression. Once the p53-mediated checkpoint is established, Rad54B is downregulated, and high checkpoint strength is maintained. Constitutive upregulation of Rad54B activity, which is frequently observed in tumours, promotes genomic instability because of checkpoint override. Thus, the scaffolding function of Rad54B dynamically regulates the maintenance of genome integrity by limiting checkpoint strength.