Excision of Environmental Carcinogen-DNA Lesions by Human NER enzymes

描述（由申请方提供）：人群暴露于环境中的致癌物质对人类健康构成重要危害。这些化学物质包括城市污染环境和香烟烟雾中的多环芳烃，以及熟食中存在的芳香胺诱变剂。这些化学物质一旦进入人体，就会被激活成与DNA化学结合的高活性中间体，从而产生庞大的加合物。后者如果不被细胞防御机制清除，可能导致突变和癌症。人体对这些环境致癌物的关键防线之一是DNA修复，特别是通过核苷酸切除修复（NER）机制来处理大量的DNA损伤。不幸的是，这种关键防御机制的分子基础，特别是它在去除重要的、结构上不同的DNA损伤方面的效率，仍然不清楚。在这个项目中，提出了一个系统的方法来解决这个问题，将确定那种致癌DNA损伤修复不良的NER机制。这一信息将是有用的生物标志物研究环境中的人类接触，并将是特别有用的，用于确定个人谁，因为遗传多态性，特别是发展癌症的风险。然后可以选择这些个体进行更密切的监测，以防止这种疾病发展到威胁生命的后期阶段。

DESCRIPTION (provided by applicant): Exposure of the human population to cancer-causing substances in the environment constitutes an important hazard to human health. Among these chemicals are polycyclic aromatic hydrocarbons in urban polluted environments and in cigarette smoke, and aromatic amines mutagens present in cooked foods. These chemicals, once they enter the human body, are activated to highly reactive intermediates that chemically bind to DNA, thus generating bulky adducts. The latter, if not removed by cellular defense mechanisms, can cause mutations and cancer. One of the critical lines of defense of the human body to these environmental carcinogens is DNA repair, specifically by the nucleotide excision repair (NER) mechanism that deals with bulky DNA damage. Unfortunately, the molecule basis of this critical defense mechanism, especially its efficiency in removing important, structurally different DNA lesions, is still obscure. In this project, a systematic approach towards solving this problem is proposed that will identify the kind of carcinogen-DNA lesions that are poorly repaired by NER mechanisms. This information will be useful in biomarker studies of environmental human exposure, and will be especially useful for identifying individuals who, because of genetic polymorphisms, are of particular risk of developing cancer. Such individuals can then be selected for closer monitoring to prevent the development of this disease into tits later life-threatening stages.