The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency:: implications for the Mre11 complex as a DNA damage sensor
The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency:: implications for the Mre11 complex as a DNA damage sensor
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DOI：
10.1101/gad.1373705
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发表时间：
2005-12-15
影响因子：
10.5
通讯作者：
Petrini, JHJ
中科院分区：
文献类型：
--
作者：
Morales, M;Theunissen, JWF;Petrini, JHJ
来自酿酒酵母和哺乳动物的遗传学和细胞学数据表明，由Mre 11、Rad 50和Nbs 1组成的Mre 11复合物是DNA损伤的传感器，并表明该复合物影响共济失调-毛细血管扩张突变（ATM）在DNA损伤反应中的活性。Rad 50（s/s）小鼠表现出造血细胞的急剧凋亡损耗。我们产生了ATM和Chk 2缺陷的Rad 50（s/s）小鼠，发现Rad 50（s/s）细胞磨损强烈依赖于ATM和Chk 2。亚纯型Mre 11（ATLD 1）和Nbs 1（Delta B）等位基因对Rad 50（s/s）依赖性造血功能衰竭具有相似的挽救作用。这些数据表明，Mre 11复合物激活ATM-Chk 2依赖性凋亡途径。我们发现细胞凋亡和细胞周期检查点激活是Mre 11复合物-ATM通路的平行结果。相反，Rad 50（s）突变减轻了ATM缺陷的几个表型特征。我们提出Rad 50（s）等位基因对于DNA损伤信号传导是超形态的，并且由此产生的DNA损伤反应的组成性低水平激活解释了Rad 50（s/s）Atm（-/-）小鼠中ATM缺陷的部分抑制。
Genetic and cytologic data from Saccharomyces cerevisiae and mammals implicate the Mre11 complex, consisting of Mre11, Rad50, and Nbs1, as a sensor of DNA damage, and indicate that the complex influences the activity of ataxia-telangiectasia mutated (ATM) in the DNA damage response. Rad50(s/s) mice exhibit precipitous apoptotic attrition of hematopoietic cells. We generated ATM- and Chk2-deficient Rad50(s/s) mice and found that Rad50(s/s) cellular attrition was strongly ATM and Chk2 dependent. The hypomorphic Mre11(ATLD1) and Nbs1(Delta B) alleles conferred similar rescue of Rad50(s/s)-dependent hematopoietic failure. These data indicate that the Mre11 complex activates an ATM-Chk2-dependent apoptotic pathway. We find that apoptosis and cell cycle checkpoint activation are parallel outcomes of the Mre11 complex-ATM pathway. Conversely, the Rad50(s) mutation mitigated several Phenotypic features of ATM deficiency. We propose that the Rad50(s) allele is hypermorphic for DNA damage signaling, and that the resulting constitutive low-level activation of the DNA damage response accounts for the partial suppression of ATM deficiency in Rad50(s/s) Atm(-/-) mice.