Germ-line variant of human NTH1 DNA glycosylase induces genomic instability and cellular transformation
Germ-line variant of human NTH1 DNA glycosylase induces genomic instability and cellular transformation
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DOI：
10.1073/pnas.1306752110
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发表时间：
2013-08-27
影响因子：
11.1
通讯作者：
Sweasy, Joann B.
中科院分区：
文献类型：
--
作者：
Galick, Heather A.;Kathe, Scott;Sweasy, Joann B.
碱基切除修复（BER）每天至少清除每个人类细胞20,000个DNA损伤，对维持基因组稳定性至关重要。我们假设，由BER基因突变引起的异常BER可导致基因组不稳定和癌症。BER的第一步是由DNA n -糖基酶催化的。其中之一，n - iii -样内切酶（NTH1），从DNA中去除氧化的嘧啶，包括胸腺嘧啶乙二醇。NTH1基因的rs3087468单核苷酸多态性是一种G-to-T碱基替换，导致NTH1 D239Y变异蛋白出现在全球6.2%的人群中，在欧洲、亚洲和撒哈拉以南非洲地区都有发现。在这项研究中，我们从功能上表征了D239Y变异在不朽但未转化的人和小鼠乳腺上皮细胞中表达的影响。我们证明，D239Y变异在表达野生型NTH1的细胞中表达会导致基因组不稳定和细胞转化，通过锚定独立生长、病灶形成、侵袭和染色体畸变来评估。我们还发现，表达D239Y变体的细胞对电离辐射和过氧化氢敏感，并在这些试剂处理后积累双链断裂。DNA损伤反应在表达d239y的细胞中也被激活。综上所述，我们的数据表明，拥有D239Y变异的个体存在基因组不稳定和癌症的风险。
Base excision repair (BER) removes at least 20,000 DNA lesions per human cell per day and is critical for the maintenance of genomic stability. We hypothesize that aberrant BER, resulting from mutations in BER genes, can lead to genomic instability and cancer. The first step in BER is catalyzed by DNA N-glycosylases. One of these, nth endonuclease III-like (NTH1), removes oxidized pyrimidines from DNA, including thymine glycol. The rs3087468 single nucleotide polymorphism of the NTH1 gene is a G-to-T base substitution that results in the NTH1 D239Y variant protein that occurs in similar to 6.2% of the global population and is found in Europeans, Asians, and sub-Saharan Africans. In this study, we functionally characterize the effect of the D239Y variant expressed in immortal but nontransformed human and mouse mammary epithelial cells. We demonstrate that expression of the D239Y variant in cells also expressing wild-type NTH1 leads to genomic instability and cellular transformation as assessed by anchorage-independent growth, focus formation, invasion, and chromosomal aberrations. We also show that cells expressing the D239Y variant are sensitive to ionizing radiation and hydrogen peroxide and accumulate double strand breaks after treatment with these agents. The DNA damage response is also activated in D239Y-expressing cells. In combination, our data suggest that individuals possessing the D239Y variant are at risk for genomic instability and cancer.