Lavin M F
Radiation Biology and Oncology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
Oncogene. 2007 Dec 10;26(56):7749-58. doi: 10.1038/sj.onc.1210880.
The recognition and repair of DNA double-strand breaks (DSBs) is a complex process that draws upon a multitude of proteins. This is not surprising since this is a lethal lesion if left unrepaired and also contributes to genome instability and the consequential risk of cancer and other pathologies. Some of the key proteins that recognize these breaks in DNA are mutated in distinct genetic disorders that predispose to agent sensitivity, genome instability, cancer predisposition and/or neurodegeneration. These include members of the Mre11 complex (Mre11/Rad50/Nbs1) and ataxia-telangiectasia (A-T) mutated (ATM), mutated in the human genetic disorder A-T. The mre11 (MRN) complex appears to be the major sensor of the breaks and subsequently recruits ATM where it is activated to phosphorylate in turn members of that complex and a variety of other proteins involved in cell-cycle control and DNA repair. The MRN complex is also upstream of ATM and ATR (A-T-mutated and rad3-related) protein in responding to agents that block DNA replication. To date, more than 30 ATM-dependent substrates have been identified in multiple pathways that maintain genome stability and reduce the risk of disease. We focus here on the relationship between ATM and the MRN complex in recognizing and responding to DNA DSBs.
DNA双链断裂(DSB)的识别与修复是一个涉及多种蛋白质的复杂过程。这并不奇怪,因为这种损伤若不修复将是致命的,还会导致基因组不稳定,进而引发癌症和其他疾病风险。一些识别DNA双链断裂的关键蛋白质在某些特定的遗传性疾病中发生突变,这些疾病易导致对药物敏感、基因组不稳定、癌症易感性和/或神经退行性变。其中包括Mre11复合物(Mre11/Rad50/Nbs1)的成员以及在人类遗传性疾病共济失调毛细血管扩张症(A-T)中发生突变的共济失调毛细血管扩张症突变基因(ATM)。Mre11(MRN)复合物似乎是双链断裂的主要感受器,随后募集ATM,ATM被激活后依次磷酸化该复合物的成员以及其他参与细胞周期调控和DNA修复的多种蛋白质。在应对阻碍DNA复制的药物时,MRN复合物也处于ATM和ATR(共济失调毛细血管扩张症突变基因和rad3相关基因)蛋白的上游。迄今为止,在维持基因组稳定性和降低疾病风险的多种途径中已鉴定出30多种依赖ATM的底物。我们在此重点关注ATM与MRN复合物在识别和应对DNA双链断裂中的关系。