Cellular Responses to DNA Damage

我们已经开发了一种体外系统，借此我们可以研究响应于DNA烷基化的ATR激酶信号级联激活的分子机制。 ATR是参与DNA损伤信号传导的磷酸肌醇3-激酶相关激酶（PIKK）家族的成员。 我们已经表明，MutSalpha和MutLalpha招募ATR的细胞毒性O 6-甲基鸟嘌呤-胸苷错配的网站，导致激活的ATR激酶活性和磷酸化的细胞周期检查点蛋白，如Chk 1和SMC 1。由p53依赖性途径介导的ATR依赖性细胞杀伤有助于DNA烷化剂的细胞毒性。 修饰的碱基类似物通常用作结直肠癌的辅助治疗，如氟尿嘧啶，目前正在研究它们是否也引起MMR依赖性细胞杀伤。

We have developed an in vitro system whereby we can study the molecular mechanism underlying activation of the ATR kinase signaling cascade in response to DNA alkylation. ATR is a member of the phosphoinositide 3-kinase-related kinase (PIKK) family involved in DNA damage signaling. We have shown that MutSalpha and MutLalpha recruit ATR to sites of cytoxic O6-methylguanine-thymidine mispairs resulting in activation of the ATR kinase activity and phosphorylation of cell cycle checkpoint proteins such as Chk1 and SMC1. ATR-dependent cell killing mediate by p53-dependent pathways contributes to the cytotoxicity of DNA alkylating agents. Modified base analogs commonly used as adjuvant therapy for colorectal cancer such as fluorouracil are currently being examined to see if they also elicit MMR-dependent cell killing.