ATM Protein-dependent Phosphorylation of Rad50 Protein Regulates DNA Repair and Cell Cycle Control
ATM Protein-dependent Phosphorylation of Rad50 Protein Regulates DNA Repair and Cell Cycle Control
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DOI：
10.1074/jbc.m111.258152
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发表时间：
2011-09-09
影响因子：
4.8
通讯作者：
Lavin, Martin F.
中科院分区：
文献类型：
--
作者：
Gatei, Magtouf;Jakob, Burkhard;Lavin, Martin F.
Mre11/Rad50/NBN复合物在协调细胞对DNA双链断裂的反应中起核心作用。Rad50在这种反应中的重要性从最近对一名Rad50缺乏患者的描述中可以明显看出，该患者的特征是染色体不稳定和atm依赖信号缺陷。我们在这里报道了ATM（失调性毛细血管扩张缺陷）在单个位点（Ser-635）磷酸化Rad50，该位点在细胞周期控制和DNA修复的信号传导中起重要的调节作用。尽管Rad50磷酸基特异性突变体（S635G）支持Rad50缺陷细胞中ATM的正常激活，但它在通过ATM依赖底物SMC1纠正DNA损伤诱导的信号传导方面存在缺陷。该突变体也无法纠正rad50缺陷细胞中的放射敏感性、DNA双链断裂修复和s期检查点缺陷。这不是由于Mre11/Rad50/NBN复合物的破坏，这首次揭示了Rad50的磷酸化作为通过SMC1进行DNA修复和细胞周期检查点控制的特定atm依赖性下游信号的适配器，在维持基因组完整性方面起着关键的调节作用。
The Mre11/Rad50/NBN complex plays a central role in coordinating the cellular response to DNA double-strand breaks. The importance of Rad50 in that response is evident from the recent description of a patient with Rad50 deficiency characterized by chromosomal instability and defective ATM-dependent signaling. We report here that ATM (defective in ataxia-telangiectasia) phosphorylates Rad50 at a single site (Ser-635) that plays an important adaptor role in signaling for cell cycle control and DNA repair. Although a Rad50 phosphosite-specific mutant (S635G) supported normal activation of ATM in Rad50-deficient cells, it was defective in correcting DNA damage-induced signaling through the ATM-dependent substrate SMC1. This mutant also failed to correct radiosensitivity, DNA double-strand break repair, and an S-phase checkpoint defect in Rad50-deficient cells. This was not due to disruption of the Mre11/Rad50/NBN complex revealing for the first time that phosphorylation of Rad50 plays a key regulatory role as an adaptor for specific ATM-dependent downstream signaling through SMC1 for DNA repair and cell cycle checkpoint control in the maintenance of genome integrity.