DNA-Protein cross-links: cellular effects and repair mechanisms

描述(申请人提供)：DNA-蛋白质交叉链接(DPC)是一种超大的、扭曲螺旋的DNA损伤，由于暴露于各种化学和物理因素，如抗肿瘤药物、环境/职业毒素、电离辐射和内源性自由基生成系统。由于DPC异常庞大的性质，它们被认为会干扰DNA复制、转录和修复所需的正常DNA-蛋白质相互作用，可能导致突变、遗传毒性和细胞毒性。然而，由于DPC损伤固有的结构复杂性，以及产生含有结构定义的DPC的DNA底物用于生物学评价的困难，人们对DPC损伤在细胞中的生物学结果知之甚少。我们的长期目标是阐明自发和诱导的DPC在人类疾病中所起的作用，以及在常见化疗药物的抗癌活性中所起的作用。这项应用的目的是确定在人类细胞中形成DPC的生物学后果，并发现负责从DNA中去除DPC的机制(S)。我们的研究将首次系统地研究DPC对DNA修复和复制的影响。我们的中心假设是，如果不修复，DPC会发挥诱变和细胞毒作用，显著促进许多已知致癌物和抗肿瘤药物的生物学效应。总的来说，这些研究将为DPC的分子和细胞生物学提供重要的新见解，并有望从根本上推动DNA修复、癌症生物学和衰老的分子机制领域的发展。

DESCRIPTION (provided by applicant): DNA-protein cross-links (DPCs) are super-bulky, helix-distorting DNA lesions that result from exposure to a variety of chemical and physical agents such as antitumor drugs, environmental/ occupational toxins, ionizing radiation, and endogenous free radical-generating systems. Due to their unusually bulky nature, DPCs are hypothesized to interfere with normal DNA-protein interactions required for DNA replication, transcription, and repair, potentially leading to mutagenesis, genotoxicity, and cytotoxicity. However, the biological outcomes of DPC lesions in cells are poorly understood because of their inherent structural complexity and the difficulty of generating DNA substrates containing structurally defined DPC for biological evaluation. Our long-term goal is to elucidate the role tha spontaneous and induced DPCs play in human disease and in the anticancer activity of common chemotherapeutic agents. The objectives of this application are to determine the biological consequences of DPC formation in human cells and to discover the mechanism(s) responsible for the removal of DPCs from DNA. Our studies will for the first time systematically examine the influence of DPCs on DNA repair and replication. Our central hypothesis is that, if not repaired, DPCs exert mutagenic and cytotoxic effects, significantly contributing to the biological effects of many known carcinogens and antitumor drugs. Collectively, these studies will provide significant new insights into the molecular and cellular biology of DPCs and are expected to fundamentally advance the fields of DNA repair, cancer biology, and molecular mechanisms of aging.