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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.

当蛋白质与DNA共价结合时，形成DNA-蛋白质交联（DPC 作为正常细胞过程如脂质过氧化、组蛋白去甲基化、DNA复制、转录和DNA修复。DPC可由以下物质诱导：暴露于抗肿瘤药物、过渡金属、UV光和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的发病率。我们目前资助的目标是应用是沿着基因组绘制DPC病变，研究人类细胞如何识别切除这些体积过大的DPC病变，并确定其机制，它们会引起突变和细胞死亡。本补充申请， DPC可能参与阿尔茨海默病和其他痴呆症。我们的中央假设是内源性醛类诱导DNA-蛋白质交联，环境金属有助于AD和其他与年龄相关的神经退行性疾病的病因疾病我们的研究计划集中在两个目标。首先，将表征DNA-蛋白质交叉- 在年龄增长的健康个体的大脑中，轻度认知能力下降的患者，阿尔茨海默病患者和非痴呆老年对照使用新的质量基于光谱的实验方法已经在我们的实验室开发。这些研究将确定参与人类大脑中DPC形成的蛋白质，并测试 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DPC在人脑中形成的机制，但与DPC相关的是，人类大脑中的重金属，内源性醛，活性氧物质。这些实验将有助于确定DNA-蛋白质交叉的来源，人类大脑的链接总的来说，我们拟议的研究将有助于今后的预防和通过提供对AD病因学的额外了解来帮助治疗努力。

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.

DNA肽和DNA-蛋白偶联物的合成和聚合酶旁路研究。

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

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

DOI：
10.1021/acschembio.9b00365
发表时间：
2019-12-20
期刊：
ACS chemical biology
影响因子：
4
作者：
Ji S;Thomforde J;Rogers C;Fu I;Broyde S;Tretyakova NY
通讯作者：
Tretyakova NY

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

Comparative Error-Free and Error-Prone Translesion Synthesis of N(2)-2'-Deoxyguanosine Adducts Formed by Mitomycin C and Its Metabolite, 2,7-Diaminomitosene, in Human Cells.

N（2）-2'-脱氧鸟氨酸加合物的无误差和容易出现的转移合成由丝裂霉素C及其代谢物在人类细胞中形成的2,7-二氨基辛素。