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Chemistry and Biology of Alkyl Phosphotriester Lesions

烷基磷酸三酯损伤的化学和生物学

基本信息

批准号：
10307544
负责人：
Yinsheng Wang
金额：
$ 36.49万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-14 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307544
关键词：
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone Affect Alkylating Agents Alkylation Biological Biological Assay Biology Bypass CRISPR/Cas technology Carcinogens Cells Chemicals Chemistry Chemotherapy-Oncologic Procedure Chromatin DNA DNA Adducts DNA Alkylation DNA Damage DNA biosynthesis DNA lesion DNA-Directed DNA Polymerase Data Development Dinucleoside Phosphates Epigenetic Process Etiology Exposure to Frequencies Genetic Transcription Health Histones Human Human Genome Induced Mutation Investigation Knowledge Lead Lesion Liver Lung Malignant Neoplasms Mammalian Cell Measures Metabolic Activation Methods Methylation Modification Molecular Mutagenesis Mutagens N&apos -nitrosonornicotine Nitrosamines Oligodeoxyribonucleotides Outcome Oxygen Rattus Research Risk Rodent Role Shuttle Vectors Site Testing Tissues Tobacco Tobacco smoke Veins Vertebral column adduct alkyl group animal tissue chemical synthesis chemotherapeutic agent design drinking water experimental study exposed human population genetic information genome editing genome integrity human disease improved inorganic phosphate insight nucleobase pyridine repaired

项目摘要

ABSTRACT The human genome is continuously attacked by a variety of endogenous and exogenous genotoxic agents, which can lead to DNA damage and compromise genomic integrity. Alkylating species constitute a ubiquitous class of DNA damaging agents. Aside from forming nucleobase adducts, alkylating agents can also attack one of the non-carbon-bonded oxygen atoms of internucleotide phosphate group to yield backbone alkylation products, i.e. the alkyl phosphotriester (alkyl-PTE) lesions. Although the alkyl-PTE lesions are induced at relatively high frequencies, very little is known about their repair and biological consequences. We hypothesize that unrepaired alkyl-PTE lesions may lead to the development of cancer and other human diseases by compromising the flow of genetic information through inhibiting DNA replication and transcription, and inducing mutations in cells. We also posit that the effects of the alkyl-PTE lesions on DNA replication and transcription may be modulated by the size of the alkyl group conjugated with the backbone phosphate in DNA. Moreover, alkylating agents are among the earliest and most widely prescribed cancer chemotherapeutic agents. Hence, a systematic investigation about how the alkyl-PTE lesions perturb DNA replication and transcription will reveal molecular insights about how exposure to alkylating agents contributes to cancer development, and provide an important knowledge basis for designing better cancer chemotherapeutic agents. To test the above hypothesis, we propose experiments according to three specific aims: Aim #1. To synthesize oligodeoxyribonucleotides (ODNs) harboring site-specifically inserted alkyl-PTE lesions with different flanking sequences; Aim #2. To investigate how the alkyl-PTE lesions perturb the efficiency and fidelity of DNA replication in cells. Aim #3. to examine the transcriptional mutagenesis and repair of alkyl-PTE lesions. The proposed research is built upon our established expertise in the chemical syntheses of lesion-carrying ODNs and in utilizing shuttle vector methods for the assessment about how DNA lesions perturb DNA replication and transcription in cells. The outcome of the proposed studies will provide a systematic and molecule-level understanding about the repair and human health consequences of the alkyl-PTE lesions. Thus, the proposed research will lead to important knowledge for assessing the risk of human exposure toward alkylating agents, for understanding the roles of these lesions in the etiology of human diseases, and for developing better strategies for cancer chemotherapy.

摘要