DNA Protein Cross-Links:Cellular Effects and Repair Mechanisms

DNA 蛋白质交联：细胞效应和修复机制

基本信息

批准号：
10713474
负责人：
COLIN R CAMPBELL
金额：
$ 37.35万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-21 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10713474
关键词：
Acceleration Address Affect Age Age-associated memory impairment Aging Aldehydes Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amyloid beta-Protein Antineoplastic Agents Autopsy Binding Biological Biological Markers Biological Process Brain Bypass Cell Death Cell physiology Cells Chemicals Chromium DNA DNA Repair DNA Repair Gene DNA biosynthesis DNA lesion DNA mapping DNA-Protein Interaction DNA-protein crosslink Dementia Development Disease Elderly Embryo Environmental Pollutants Etiology Excision Exposure to Failure Fibroblasts Formaldehyde Funding Future Gamma Rays Genetic Genetic Recombination Genetic Transcription Genome Genomic DNA Genomic Instability Germ-Line Mutation Goals Heavy Metals Histones Human Impaired cognition Incidence Individual Inductively Coupled Plasma Mass Spectrometry Ionizing radiation Laboratories Lesion Lipid Peroxidation Malignant Neoplasms Mass Spectrum Analysis Measures Metabolism Metals Methodology Mouse Strains Mus Nature Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Nickel Normal Cell Nucleotide Excision Repair Occupational Pathology Pathway interactions Patients Peptide Hydrolases Peptides Phenotype Prefrontal Cortex Prevention Prevention strategy Primary carcinoma of the liver cells Proteins Reactive Oxygen Species Research Role Sampling Site Solubility Source Structure Syndrome Techniques Testing Toxic Environmental Substances Transition Elements Ultraviolet Rays abeta deposition adverse outcome age related age related neurodegeneration aged antitumor drug brain tissue cognitive function demethylation disability early onset experimental study frontal lobe hyperphosphorylated tau insight neuron loss non-demented novel novel strategies polyanion polycation protein aggregation repaired senescence tau Proteins

项目摘要

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.

DNA-蛋白交联（DPC）是在蛋白质共价结合DNA时形成的由于正常的细胞过程（例如脂质过氧化，组蛋白去甲基化，DNA复制，转录和DNA修复。 DPC可以由暴露于抗肿瘤药物，过渡金属，紫外线和γ辐射。 DPC干扰许多生物过程，在加速衰老和癌症增加中暗示在Ruijs-AALFS综合征患者中观察到的发病率。我们目前资助的目标应用是沿基因组绘制DPC病变，研究人类细胞如何识别并清除这些极大的DPC病变，并确定该机制它们会导致诱变和细胞死亡。目前的补充申请，地址为 DPC在阿尔茨海默氏病和其他痴呆症中的潜在参与。我们的中心假设是由内源性醛诱导的DNA-蛋白质交联和环境金属有助于AD和其他与年龄有关的神经退行性的病因疾病。我们的研究计划侧重于两个目标。首先，将表征DNA-蛋白交叉与年龄增长的健康个体，轻度认知能力下降的患者联系在一起，阿尔茨海默氏病患者，并使用新型质量进行了非旧对照基于光谱的实验方法已经在我们的实验室中开发了。这些研究将确定参与人脑DPC形成的蛋白质并测试A DNA-蛋白质交联与衰老和神经退行性疾病的可能关联。其次，我们将确定人脑中DPC形成的机制，但与DPC相关人脑的水平达到重金属，内源性醛和活性氧。这些实验将有助于确定DNA-蛋白质交叉的来源人脑中的链接。总的来说，我们提出的研究将促进未来的预防和通过提供对AD病因的更多见解，通过提供治疗工作。

项目成果

期刊论文数量（30）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synthesis and polymerase bypass studies of DNA-peptide and DNA-protein conjugates.

DOI：
10.1016/bs.mie.2021.09.005
发表时间：
2021
期刊：
Methods in enzymology
影响因子：
0
作者：
通讯作者：

5-Formylcytosine mediated DNA-protein cross-links block DNA replication and induce mutations in human cells.

DOI：
10.1093/nar/gky444
发表时间：
2018-07-27
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Ji S;Fu I;Naldiga S;Shao H;Basu AK;Broyde S;Tretyakova NY
通讯作者：
Tretyakova NY

Controlling the Graphene-Bio Interface: Dispersions in Animal Sera for Enhanced Stability and Reduced Toxicity.

DOI：
10.1021/acs.langmuir.7b02854
发表时间：
2017-12-12
期刊：
Langmuir : the ACS journal of surfaces and colloids
影响因子：
0
作者：
Pattammattel A;Pande P;Kuttappan D;Puglia M;Basu AK;Amalaradjou MA;Kumar CV
通讯作者：
Kumar CV

Investigation into Propolis Components Responsible for Inducing Skin Allergy: Air Oxidation of Caffeic Acid and Its Esters Contribute to Hapten Formation.

DOI：
10.1021/acs.chemrestox.2c00386
发表时间：
2023-06-19
期刊：
CHEMICAL RESEARCH IN TOXICOLOGY
影响因子：
4.1
作者：
Ndreu, Lorena;Hurben, Alexander K.;Nyman, Gunnar S. A.;Tretyakova, Natalia Y.;Karlsson, Isabella;Hagvall, Lina
通讯作者：
Hagvall, Lina

Transcriptional Bypass of DNA-Protein and DNA-Peptide Conjugates by T7 RNA Polymerase.