DNA Protein Cross-Links:Cellular Effects and Repair Mechanisms

DNA-蛋白质交联链(DPC)是当蛋白质与DNA共价结合时形成的 在正常的细胞过程中自发形成，如脂质过氧化、组蛋白 去甲基化、DNA复制、转录和DNA修复。DPC可通过以下方式诱导 暴露于抗肿瘤药物、过渡金属、紫外线和γ辐射。DPC干扰 许多生物过程，并与加速衰老和增加癌症有关 在Ruijs-Aalfs综合征患者中观察到发病率。我们目前资助的目标是 应用是沿着基因组绘制DPC损伤图，研究人类细胞如何识别 并移除这些极大的DPC病变，并确定其机制 它们会导致突变和细胞死亡。本补充申请的地址为 DPC可能与阿尔茨海默病和其他痴呆症有关。我们的中央 假说是由内源性醛和蛋白质引起的DNA-蛋白质交联 环境金属在AD和其他与年龄相关的神经退行性变的病因中起作用 疾病。我们的研究计划集中在两个目标上。首先，将表征DNA-蛋白质交叉- 与年龄增长的健康个体、轻度认知功能减退患者的大脑相关， 阿尔茨海默病患者和使用新质量的非痴呆症老年人对照 我们实验室已经开发了基于光谱学的实验方法。这些 研究将确定参与人脑DPC形成的蛋白质，并测试 DNA-蛋白质交联可能与衰老和神经退行性疾病有关。 第二，我们将确定人脑中DPC的形成机制，但与DPC相关 人类大脑中的重金属、内源性醛和 活性氧物种。这些实验将有助于确定DNA-蛋白质交叉反应的来源 人脑中的联系。总的来说，我们建议的研究将促进未来的预防和 通过提供对阿尔茨海默病病因的更多洞察力来进行治疗。

DNA-protein cross-links (DPCs) are formed when proteins become covalently bound to DNA form spontaneously as a result of normal cellular processes such as lipid peroxidation, histone demethylation, DNA replication, transcription, and DNA repair. DPCs can be induced by exposure to anti-tumor drugs, transition metals, UV light, and γ-radiation. DPCs interfere with many biological processes and are implicated in the accelerated aging and increased cancer incidence observed in Ruijs-Aalfs syndrome patients. The goal of our currently funded application is to map DPC lesions along the genome, investigate how human cells recognize and remove these exceedingly bulky DPC lesions, and to identify the mechanisms by which they cause mutagenicity and cell death. The present supplement application with address the potential involvement of DPCs in Alzheimer’s disease and other dementias. Our central hypothesis is that that DNA-protein cross-linking induced by endogenous aldehydes and environmental metals contribute to the etiology of AD and other age-related neurodegenerative diseases. Our research plan focuses on two Aims. First, will characterize DNA-protein cross- linking in brains of healthy individuals of increasing age, patients with mild cognitive decline, Alzheimers’s disease patients, and nondemented elderly controls using novel mass spectrometry based experimental methodologies already developed in our laboratory. These studies will identify the proteins participating in DPC formation in human brain and test a possible association of DNA-protein cross-linking with aging and neurodegenerative disease. Second, we will identify the mechanisms of DPC formation in human brain but correlating DPC levels in human brain to the concentrations of heavy metals, endogenous aldehydes, and reactive oxygen species. These experiments will help identify the sources of DNA-protein cross- links in human brain. Collectively, our proposed studies will facilitative future prevention and treatment efforts by providing additional insight into the etiology of AD.