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Role of XPD in DNA Damage Response Pathway Choice

XPD 在 DNA 损伤反应途径选择中的作用

基本信息

批准号：
10531035
负责人：
Faye A Rogers
金额：
$ 38.82万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10531035
关键词：
Address Apoptosis Apoptotic Cell Cycle Arrest Cell Death Cell Survival Cells Cessation of life Chemicals Complex DNA Damage DNA Repair DNA lesion Data Disease Equilibrium Etiology Exposure to Funding Genetic Diseases Genetic Transcription Genome Genome Stability Genomic Instability Genotoxic Stress Goals Human Genetics Human Genome Lead Lesion Link Location Maintenance Malignant Neoplasms Mediating Molecular Mutagenesis Mutagens Mutation Nucleotide Excision Repair Outcome Pathway interactions Phenotype Phosphorylation Positioning Attribute Process Property Protein Tyrosine Kinase Proteins Reaction Regulation Research Research Project Grants Role Series Signal Pathway Signal Transduction Site Structure System TP53 gene Tyrosine Tyrosine Phosphorylation Work cancer risk chemotherapeutic agent crosslink design driving force experimental study genome integrity genotoxicity helicase human disease insight mouse model novel preservation prevent programs recruit repair function repaired response tool transcription factor TFIIH

项目摘要

PROJECT SUMMARY. Role of XPD in DNA Damage Response Pathway Choice The DNA damage response has evolved to protect the integrity of the human genome against the potentially devastating effects of endogenous and exogenous genotoxins. A successful DNA damage response occurs due to well-orchestrated crosstalk between pathways within the network. For instance, an intricate balance between DNA repair and apoptosis minimizes the likelihood of genomic instability, which can lead to mutagenesis and ultimately to disease. Although the regulatory mechanism and signaling pathways controlling DNA repair and apoptosis are well characterized, the driving forces responsible for making the ultimate choice between DNA repair and apoptosis in response to genotoxic stress remain unclear. The overall goal is to understand the mechanisms involved in triggering the appropriate reaction at the intersection of the nucleotide excision repair (NER) and apoptotic pathways. The NER pathway occupies an important position in the recognition and repair of a wide array of helix- distorting lesions, including formation of triplex structures and lesions generated by chemotherapeutic agents. Recent work from our group has discovered that the NER protein, XPD occupies a central role in triggering p53- independent apoptosis in response to helix-distorting DNA damage via phosphorylation of the H2AX tyrosine142 residue. In Aim 1, we will determine how XPD tyrosine phosphorylation functions as a signaling mechanism to mediate DNA repair-apoptosis pathway choice. In Aim 2, we will determine whether XPD’s role in cell fate decisions is linked to its molecular properties essential for repair, transcription, and apoptosis. The proposed work is highly significant because imbalance between pathways within the DNA damage response network can eventually contribute to the etiology of human diseases.

项目总结。XPD在DNA损伤反应途径选择中的作用