Characterization of rare NEIL1 variants found in East Asian populations
Characterization of rare NEIL1 variants found in East Asian populations
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DOI：
10.1016/j.dnarep.2019.05.001
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发表时间：
2019-07-01
期刊：
影响因子：
3.8
通讯作者：
Lloyd, R. Stephen
中科院分区：
文献类型：
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作者：
Minko, Irina G.;Vartanian, Vladimir L.;Lloyd, R. Stephen
长期饮食暴露于真菌毒素黄曲霉毒素B-1（AF B（1））和B型肝炎病毒（HBV）感染与早发性肝细胞癌（HCC）风险增加相关。深入了解致癌机制对于识别影响HBV感染和AFB（1）暴露个体易感性的遗传风险因素至关重要。AFB（1）诱导的突变以G到T颠换为特征。因此，对AFB（1）诱导的DNA加合物或HBV诱导的炎症引起的碱基损伤起作用的DNA修复途径预计在限制致癌作用方面具有重要作用。这些途径定义了靶组织中的致突变负荷，并最终限制了细胞向癌症的进展。小鼠数据表明，相对于肝癌诱导风险的升高，DNA碱基切除修复途径中的NEIL 1比核苷酸切除修复显著更重要。这些数据表明，NEIL 1的缺陷可能导致人类HCC的发生。为了研究这一假设，分析了NEIL 1变异等位基因的公开数据，并与来自启东县（中国）个体的HCC组织的基因组测序数据进行了比较。鉴定了三种变异等位基因，并对相应的A51 V、P68 H和G245 R酶在含有一系列氧化诱导碱基损伤的基因组DNA和含有位点特异性AFB（1）-甲酰氨基嘧啶鸟嘌呤加合物的寡脱氧核苷酸上的糖基化酶活性进行了表征。尽管P68 H变体的效率适度降低，但A51 V和G245 R变体显示出接近野生型的活性。与生化研究结果一致，这些变体的分子建模仅表现出轻微的局部结构改变。然而，A51 V对温度高度敏感，这表明其生物活性会大大降低。总的来说，这些研究与人类健康直接相关，涉及遗传风险因素和以前未被认为与HCC诱导密切相关的生化途径。
The combination of chronic dietary exposure to the fungal toxin, aflatoxin B-1 (AFB(1)), and hepatitis B viral (HBV) infection is associated with an increased risk for early onset hepatocellular carcinomas (HCCs). An in-depth knowledge of the mechanisms driving carcinogenesis is critical for the identification of genetic risk factors affecting the susceptibility of individuals who are HBV infected and AFB(1) exposed. AFB(1)-induced mutagenesis is characterized by G to T transversions. Hence, the DNA repair pathways that function on AFB(1)-induced DNA adducts or base damage from HBV-induced inflammation are anticipated to have a strong role in limiting carcinogenesis. These pathways define the mutagenic burden in the target tissues and ultimately limit cellular progression to cancer. Murine data have demonstrated that NEIL1 in the DNA base excision repair pathway was significantly more important than nucleotide excision repair relative to elevated risk for induction of HCCs. These data suggest that deficiencies in NEIL1 could contribute to the initiation of HCCs in humans. To investigate this hypothesis, publicly-available data on variant alleles of NEIL1 were analyzed and compared with genome sequencing data from HCC tissues derived from individuals residing in Qidong County (China). Three variant alleles were identified and the corresponding A51V, P68H, and G245R enzymes were characterized for glycosylase activity on genomic DNA containing a spectrum of oxidatively-induced base damage and an oligodeox-ynucleotide containing a site-specific AFB(1)-formamidopyrimidine guanine adduct. Although the efficiency of the P68H variant was modestly decreased, the A51V and G245R variants showed nearly wild-type activities. Consistent with biochemical findings, molecular modeling of these variants demonstrated only slight local structural alterations. However, A51V was highly temperature sensitive suggesting that its biological activity would be greatly reduced. Overall, these studies have direct human health relevance pertaining to genetic risk factors and biochemical pathways previously not recognized as germane to induction of HCCs.