在DNA损伤修复中解螺旋酶的作用机理

Environmental cancer-causing PAH compounds such as benzo[a]pyrene (BP) are found at toxic waste dumps and superfund sites, in airborne particulates, water, food, vehicle exhaust, and tobacco smoke. DNA adducts derived from metabolically activated BP diol epoxides have been found in tissues of ~ 30-50% of all smokers, and to lesser extents in tissues of non-smokers, former smokers, occupationally exposed individuals, and people exposed to PAH-contaminated environments. PAH compounds are believed to be responsible for the higher rates of lung and other cancers that have been documented in smokers and residents of urban areas. The human nucleotide excision repair system is the major cellular defense mechanism that removes bulky DNA lesions from the genome. However, some DNA lesions are known to evade repair because they are not recognized or poorly recognized by the NER system, and are therefore a particular threat to human health. DNA repair capacity is likely to be one of the key factors that determine cancer initiating potential, and therefore in vitro assessments of NER efficiencies may be useful for predicting the risk of individuals to exposure to carcinogens in the workplace or environment. Since NER protects the human genome from a wide spectrum of endogenous and exogenous chemical insults, it is essential to unravel the sophisticated mechanism at a molecular level that the NER machinery uses to recognize DNA lesions. Understanding why certain DNA lesions are resistant to NER, could lead to the development of better targeted biomarkers of environmental exposure to health-threatening genotoxic chemicals that persist and might accumulate in human tissues.

癌症现在已经成为威胁人类健康的重大疾病，而绝大多数的癌症被认为与环境有关。因为我们生活的环境中有很多的致癌物质比如多芳烃化合物。人类的核苷酸剪切修复机制可以帮助人类基因修复DNA损伤，其含有众多蛋白修复因子并执行不同功能。我们期望通过研究来进一步搞清楚NER修复机制中解螺旋步骤的机理。而且，通过对于不同DNA加合物体外核苷酸切除修复效率的研究有助于预测人们暴露在含有致癌DNA加合物的工作场所或环境中是否存在致癌风险。此外，通过研究那些会在人体组织积聚的对威胁人类健康的并且不能够被核苷酸切除修复的DNA损伤，可以帮助我们设计针对性的生物探针来治疗癌症。