权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The mutagenic consequences of replication-coupled DNA repair mechanisms

复制耦合 DNA 修复机制的致突变后果

基本信息

批准号：
10893196
负责人：
Kavi Mehta
金额：
$ 24.9万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-09 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10893196
关键词：
4-Hydroxy-Tamoxifen Aging Agrochemicals Air Pollution Alkylating Agents Aromatic Amines Aromatic Polycyclic Hydrocarbons Bacillus subtilis Binding Biological Assay Biological Models Bypass CRISPR screen Cell Nucleus Cells Chemicals Clustered Regularly Interspaced Short Palindromic Repeats Copy Number Polymorphism Coupled Cysteine Cytidine Deaminase Cytoprotection Cytosine DNA DNA Repair DNA Sequence Rearrangement DNA biosynthesis DNA lesion DNA-(apurinic or apyrimidinic site) lyase DNA-Directed DNA Polymerase DNA-protein crosslink Data Deamination Estrogen Receptors Event Food Foundations Frequencies Future Genetic Genome Stability Genomic Instability Genomics Goals Human Hyperactivity Industrialization Institution Learning Lesion Malignant Neoplasms Mammalian Cell Methods Mutagenesis Mutagens Mutation N-terminal Pathway interactions Peptide Hydrolases Pharmaceutical Preparations Phase Plasmids Polymerase Principal Investigator Process Proteins Research Series Signal Transduction Single-Stranded DNA Site Source Specific qualifier value Specificity Stress System Testing Toxic Environmental Substances Toxin Training Uracil Water Work adduct base biological adaptation to stress career crosslink deep sequencing developmental disease endonuclease environmental toxicology exome sequencing inhibitor innovation insertion/deletion mutation lens multicatalytic endopeptidase complex mutant oxidation prevent protective pathway recruit repaired replication stress response uracil-DNA glycosylase

项目摘要

Project Summary Environmental genotoxins such as oxidation agents, alkylating agents, aromatic amines, crosslinking agents, polycyclic aromatic hydrocarbons, and natural toxins induce a full spectrum of DNA lesions including abasic sites, interstrand crosslinks, and bulky DNA base adducts. These environmental genotoxins are found in our waterways, food, industrial and agricultural chemicals, and air pollution and have the potential to induce mutagenesis and genomic instability if genetic lesions are not repaired. Mutagenesis and genomic instability can lead to developmental disorders, aging, and cancers. HMCES is a replication-coupled repair protein that responds to single-strand DNA abasic sites and prevents their cleavage by AP-endonucleases. Abasic sites are a common lesion caused by environmental genotoxins. My preliminary results suggest that HMCES prevents both genomic instability and mutagenesis, and I hypothesize that it promotes a more faithful repair mechanism such as template switching or fork reversal. For the K99-phase of this proposal I will learn to perform short and long-term mutagenesis assays and DNA deep sequencing methods to understand in detail how HMCES prevents mutagenesis and genomic instability in human cells and promotes more error-free repair. This work will create a technical foundation and blueprint for studies (R00) characterizing the strand-specific replication stress response and how strand-specific obstacles and environmental genotoxins contribute to leading and lagging strand mutagenesis. There are core differences between replication on the leading and lagging strands. DNA replication occurs continuously on the leading strand and discontinuously on the lagging strand through a series of repriming events. I hypothesize that strand-specific lesions and obstacles generate a differential replication stress response, and potentiate mutagenesis differently. I will characterize the lagging and leading strand stress responses using unbiased approaches. Further, I will determine the consequences of strand-specific stress and genotoxins on mutagenic strand bias using deep sequencing-based mutagenesis assays. Ultimately, this proposal will advance the environmental toxicology and DNA repair fields leading to paradigm shifting discoveries.

项目总结