Functions of SRAP domain proteins in DNA metabolism

SRAP结构域蛋白在DNA代谢中的功能

• 批准号: 9751009
• 负责人: David K Cortez
• 金额: $ 43.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751009
• 关键词: Aging; Agrochemicals; Air Pollution; Alkylating Agents; Alkylation; Bacteria; Binding; Biochemical; Biochemical Genetics; Bypass; Carbon; Cells; Chemicals; Chloroform; Clinical; Coupled; Cysteine; Cytosine; DNA; DNA Binding; DNA Damage; DNA Repair; DNA Repair Gene; DNA Repair Pathway; DNA biosynthesis; DNA lesion; DNA replication fork; DNA-Directed DNA Polymerase; DNA-protein crosslink; Data; Detergents; Diet; Disease; Environmental Exposure; Enzymatic Biochemistry; Epigenetic Process; Exposure to; Failure; Food; Frequencies; Future; Gene Expression; Genes; Genetic; Genetic Screening; Genetic Structures; Genome; Genome Stability; Genotoxic Stress; Guanine; Human; Hydroxyl Radical; Hypersensitivity; Ionizing radiation; Knock-out; Lesion; Life; Ligands; Link; Maintenance; Malignant Neoplasms; Metabolism; Methods; Modeling; Mutagenesis; Mutagens; Mutation; N-terminal; Nitrosamines; Organism; Oxidants; Oxidative Stress; Oxides; Pathway interactions; Peptide Hydrolases; Phenotype; Plastics; Polymerase; Process; Proteins; Proteomics; Radiation; Reporting; Resolution; S Phase; SOS Response; SS DNA BP; Saccharomyces cerevisiae; Single-Stranded DNA; Site; Solvents; Source; Structure; System; Tertiary Protein Structure; Testing; Therapeutic Intervention; Toxic Environmental Substances; UV Radiation Exposure; Yeasts; adduct; base; blastomere structure; crosslink; endonuclease; environmental toxicology; experimental study; fitness; genetic approach; genome integrity; innovation; loss of function; nuclease; oxidation; potassium bromate; prevent; protein crosslink; protein function; recruit; repair enzyme; repaired; response; suicide enzyme; targeted treatment

PROJECT SUMMARY Thousands of abasic sites form daily in each of our cells. Many types of environmental toxins that cause alkylation or oxidation of DNA bases to form N7-guanine adducts and 8-oxoguanine induce abasic sites. For example, N-nitrosamines that are found in foods, detergents, solvents, plastics, and agricultural chemicals as well as chemicals like carbon tetracholoride, potassium bromate, and chloroform that induce oxidative stress all increase the frequency of abasic sites in DNA. Failures in managing this ubiquitous form of DNA damage can cause a variety of diseases including cancer. The known mechanisms of repair require an intact DNA duplex; however, abasic sites form more readily in single-stranded DNA where they are impediments to replicative polymerases. We utilized unbiased proteomic and genetic approaches to understand how replication forks deal with challenges to genotoxic stresses with the premise that uncharacterized proteins identified in both approaches would be strong candidates for new DNA damage response proteins. Both the proteomic and genetic screens identified HMCES (hydroxyl-methyl cytosine embryonic cell specific) as a candidate genome maintenance protein functioning at replication forks. HMCES was reported to bind and remove 5-hydroxymethyl cytosine from DNA and thereby regulate gene expression. Our preliminary data suggests that HMCES independently functions as a replication- associated DNA repair protein. HMCES contains an evolutionarily ancient domain (SRAP). We hypothesize that SRAP proteins provide a mechanism to repair or tolerate DNA damage during DNA replication. This proposal will utilize biochemical, genetic, and structural approaches in human, yeast, and bacterial systems to determine how SRAP proteins maintain genome stability. Completing these studies will generate paradigm setting discoveries within the fields of environmental toxicology, DNA repair, DNA replication, epigenetic control, and enzymology.

项目总结