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The role of And-1 in nucleotide excision repair

And-1在核苷酸切除修复中的作用

基本信息

批准号：
10362967
负责人：
Wenge Zhu
金额：
$ 45.58万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-17 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10362967
关键词：
Affect Animal Model Binding Cell Cycle Cells Chromosomal Stability Complement DBL Oncoprotein DNA Damage DNA Repair DNA biosynthesis DNA lesion DNA-Binding Proteins DNA-Directed DNA Polymerase Data Dermal Excision Repair Fibroblasts Future Genes Genome Genome Stability Hypersensitivity Knowledge Lesion Ligation Link Malignant Neoplasms Mammals Mediating Molecular Mus Mutate Mutation Nuclear Nucleotide Excision Repair Nucleotides Orthologous Gene Pathway interactions Patients Phosphorylation Physiological Play Polymerase Positioning Attribute Precision therapeutics Process Protein Conformation Proteins Regulation Regulatory Pathway Role Series Single-Stranded DNA Site Skin Skin Cancer Skin Neoplasms Testing Time Transcription-Coupled Repair UV induced UV induced DNA damage Ultraviolet Rays Xeroderma Pigmentosum Yeasts chemotherapeutic agent design environmental mutagens experimental study gene repair homologous recombination in vivo individualized prevention mouse model multidisciplinary novel recombinational repair recruit repaired response skin squamous cell carcinoma therapeutic development tumorigenesis ultraviolet irradiation ultraviolet lesions

项目摘要

Project Summary Nucleotide excision repair (NER) is the major pathway to remove bulky DNA lesions induced by UV irradiation, environmental mutagens, and chemotherapeutic agents. Deficiency of genes involved in NER has been linked to Xeroderma Pigmentosum (XP) and skin cancer. There are two mechanisms to detect DNA damage by NER, one is global genome NER(GG-NER) and another is transcription-coupled NER(TC-NER). GG-NER occurs anywhere in the genome, whereas TC-NER is responsible for the accelerated repair of lesions in the transcribed strand of active genes. The both pathways are divided into early and late steps. The early step is the sequential actions, in which XP proteins recognize, unwind, and incise the DNA lesion. The latter step is identical in both mechanisms and is characterized by gap-filling repair synthesis, in which DNA replication proteins fill in the ~30 nucleotide gap, followed by ligation. Compared to the well-characterized early step, the molecular mechanism regulating the activation of gap-filling DNA synthesis at late step remains largely unknown. Even less is known about the physiological impact of such a regulatory pathway. And-1 is an acidic nucleoplasmic DNA-binding protein and its yeast ortholog, Ctf4, was originally identified as a critical gene for chromosome stability. Interestingly, yeast cells with depletion of Ctf4 gene are hypersensitive to UV lights, suggesting a role of And-1 in UV-induced DNA damage response. However, how And-1 regulates NER remains largely unknown. In this study, we now have extensive preliminary data demonstrating that And-1 is critical for NER by regulating gap-filling DNA synthesis. Our hypothesis is that And-1 regulates DNA polymerase activity at UV-lesion sites to activate gap-filling DNA synthesis at the late stage of NER. To test this hypothesis, we plan to pursue three specific aims. Aim 1: Determine the mechanism by which And-1 regulates DNA polymerase activity in NER. Aim 2: Determine the unique mechanism by which And-1 is recruited to UV-lesion sites. Aim 3: Determine the role of And-1 in NER and skin tumorigenesis using And-1 deficient mouse models. The completion of proposed studies will not only advance the field by uncovering a novel And-1-mediated pathway to regulate NER, but also provide us with the in vivo evidence to elucidate a novel role of And-1 in NER and skin tumor.

项目总结