Key Laboratory of Chinese Ministry of Agriculture for Nuclear-Agricultural Sciences, Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou, China.
Oncogene. 2011 Mar 3;30(9):1072-81. doi: 10.1038/onc.2010.482. Epub 2010 Oct 25.
A critical observation in sporadic cancers is that not all individuals are equally prone to developing cancer following exposure to a given environmental carcinogen. Epidemiological studies have suggested that the difference in the timing of cancer onset in response to exogenous DNA damage is likely attributable to genetic variations, such as those associated with base excision repair (BER) genes. To test this long-standing hypothesis and elucidate how a genetic variation in the BER gene flap endonuclease 1 (FEN1) results in susceptibility to environment insults and causes cancer, we established a mutant mouse model carrying a point mutation (E160D) in Fen1. We demonstrate that the E160D mutation impairs the ability of FEN1 to process DNA intermediate structures in long-patch BER using nuclear extracts or reconstituted purified BER proteins. E160D cells were more sensitive to the base-damaging agents methylnitrosourea and hydrogen peroxide, leading to DNA strand breaks, chromosomal breakage and chromosome instabilities in response these DNA insults. We further show that E160D mice are significantly more susceptible to exposure to methylnitrosourea and develop lung adenocarcinoma. Thus, our current study demonstrates that a subtle genetic variation (E160D) in BER genes (FEN1) may cause a functional deficiency in repairing base damage, such that individuals carrying the mutation or similar mutations are predisposed to chemical-induced cancer development.
在散发性癌症中,一个关键的观察结果是,并非所有个体在暴露于特定环境致癌物后都会同样容易患上癌症。流行病学研究表明,对外源性 DNA 损伤的癌症起始时间的差异可能归因于遗传变异,例如与碱基切除修复 (BER) 基因相关的那些变异。为了检验这一长期存在的假说,并阐明 BER 基因切刻内切酶 1 (FEN1) 中的遗传变异如何导致对环境损伤的易感性并导致癌症,我们建立了携带 FEN1 点突变 (E160D) 的突变小鼠模型。我们证明,E160D 突变会损害 FEN1 在长补丁 BER 中处理 DNA 中间结构的能力,使用核提取物或重新组成的纯化 BER 蛋白。E160D 细胞对碱基损伤剂甲基亚硝脲和过氧化氢更敏感,导致 DNA 链断裂、染色体断裂和染色体不稳定,以响应这些 DNA 损伤。我们进一步表明,E160D 小鼠对甲基亚硝脲的暴露更敏感,并发展为肺腺癌。因此,我们目前的研究表明,BER 基因 (FEN1) 中的微小遗传变异 (E160D) 可能导致修复碱基损伤的功能缺陷,使得携带该突变或类似突变的个体易患化学诱导的癌症发展。