Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11
Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11
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DOI：
10.1073/pnas.1306328110
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发表时间：
2013-12-17
影响因子：
11.1
通讯作者：
Kornbluth, Sally
中科院分区：
文献类型：
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作者：
Chen, Chen;Zhang, Liguo;Kornbluth, Sally
共济失调毛细血管扩张突变体（ATM）是一种S/ t - q定向激酶，对细胞对DNA双链断裂（DSBs）的反应至关重要。在DNA损伤后，ATM被MRN蛋白复合物[减数分裂重组11 (Mre11)/DNA修复蛋白Rad50/奈梅根断裂综合征1蛋白]激活并招募到DNA损伤位点，在那里ATM磷酸化多种底物以触发细胞周期阻滞。在癌细胞中，这种调节可能是错误的，即使存在受损的DNA，细胞分裂也可能继续进行。我们在这里表明，核糖体s6激酶（Rsk）在癌症中经常升高，可以抑制dsb诱导的ATM激活，无论是在爪蟾卵提取物还是人类肿瘤细胞系中。在分析ATM激活的每个步骤时，我们发现Rsk的目标是在DSB位点将MRN复合物组分加载到DNA上。Rsk可以在体外和完整细胞中直接磷酸化Mre11蛋白的S676位点，从而抑制Mre11与dsb结合DNA。因此，S676对Ala的突变可以逆转风险对DSBs反应的抑制。总的来说，这些数据表明Mre11是rsk介导的检查点抑制作用于ATM激活上游的一个重要位点。
Ataxia telangiectasia mutant (ATM) is an S/T-Q-directed kinase that is critical for the cellular response to double-stranded breaks (DSBs) in DNA. Following DNA damage, ATM is activated and recruited by the MRN protein complex [meiotic recombination 11 (Mre11)/DNA repair protein Rad50/Nijmegen breakage syndrome 1 proteins] to sites of DNA damage where ATM phosphorylates multiple substrates to trigger cell-cycle arrest. In cancer cells, this regulation may be faulty, and cell division may proceed even in the presence of damaged DNA. We show here that the ribosomal s6 kinase (Rsk), often elevated in cancers, can suppress DSB-induced ATM activation in both Xenopus egg extracts and human tumor cell lines. In analyzing each step in ATM activation, we have found that Rsk targets loading of MRN complex components onto DNA at DSB sites. Rsk can phosphorylate the Mre11 protein directly at S676 both in vitro and in intact cells and thereby can inhibit the binding of Mre11 to DNA with DSBs. Accordingly, mutation of S676 to Ala can reverse inhibition of the response to DSBs by Rsk. Collectively, these data point to Mre11 as an important locus of Rsk-mediated checkpoint inhibition acting upstream of ATM activation.