Cancer Research UK Gene Function and Regulation Group, The Institute of Cancer Research, London SW3 6JB, UK.
Cancer Cell. 2010 Mar 16;17(3):235-48. doi: 10.1016/j.ccr.2009.12.046.
Synthetic sickness/lethality (SSL) can be exploited to develop therapeutic strategies for cancer. Deficiencies in the tumor suppressor proteins MLH1 and MSH2 have been implicated in cancer. Here we demonstrate that deficiency in MSH2 is SSL with inhibition of the DNA polymerase POLB, whereas deficiency in MLH1 is SSL with DNA polymerase POLG inhibition. Both SSLs led to the accumulation of 8-oxoG oxidative DNA lesions. MSH2/POLB SSL caused nuclear 8-oxoG accumulation, whereas MLH1/POLG SSL led to a rise in mitochondrial 8-oxoG levels. Both SSLs were rescued by silencing the adenine glycosylase MUTYH, suggesting that lethality could be caused by the formation of lethal DNA breaks upon 8-oxoG accumulation. These data suggest targeted, mechanism-based therapeutic approaches.
合成疾病/致死性（SSL）可被利用来开发癌症的治疗策略。肿瘤抑制蛋白 MLH1 和 MSH2 的缺陷与癌症有关。在这里，我们证明 MSH2 的缺陷是 SSL，伴随着 DNA 聚合酶 POLB 的抑制，而 MLH1 的缺陷是 SSL，伴随着 DNA 聚合酶 POLG 的抑制。这两种 SSL 都会导致 8-oxoG 氧化 DNA 损伤的积累。MSH2/POLB SSL 导致核 8-oxoG 积累，而 MLH1/POLG SSL 导致线粒体 8-oxoG 水平升高。这两种 SSL 都可以通过沉默腺嘌呤糖苷酶 MUTYH 来挽救，这表明致死性可能是由于 8-oxoG 积累形成致死性 DNA 断裂引起的。这些数据表明了有针对性的、基于机制的治疗方法。
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