Excision of Environmental Carcinogen-DNA Lesions by Human NER enzymes

描述(申请人提供)：人类接触环境中的致癌物质对人类健康构成重大危害。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，就会被激活为高活性的中间体，与DNA化学结合，从而产生大量的加合物。后者，如果不被细胞防御机制消除，可能会导致突变和癌症。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)机制来处理巨大的DNA损伤。不幸的是，这一关键防御机制的分子基础，特别是它在消除重要的、结构不同的DNA损伤方面的效率，仍然不清楚。在这个项目中，提出了一种系统的方法来解决这个问题，它将识别出NER机制修复不佳的致癌物-DNA损伤的类型。这些信息将在环境人类暴露的生物标记物研究中有用，并将特别有助于识别由于基因多态而具有患癌症特别风险的个人。然后可以选择这些人进行更密切的监测，以防止这种疾病在以后发展为危及生命的阶段。

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.