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

Roles of the nucleic acid motor protein ZGRF1 in chromosome damage repair

核酸马达蛋白ZGRF1在染色体损伤修复中的作用

基本信息

批准号：
9753247
负责人：
Patrick Sung
金额：
$ 22.88万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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：
2018-08-15 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753247
关键词：
ATP phosphohydrolase Affect Air Pollutants BARD1 gene BRCA1 gene BRCA2 gene Biochemical Biochemical Genetics Biological Biological Process Cancer Etiology Cells Chemicals Chromosome abnormality Chromosomes Co-Immunoprecipitations Cytology DNA DNA Damage DNA Double Strand Break DNA Repair DNA biosynthesis DNA crosslink DNA replication fork DNA-dependent ATPase Defect Development Disease Dissociation Engineering Exposure to Genetic Genetic Transcription Genome Genomics Goals Heavy Metals Human Hypersensitivity Impairment Lead Length Lesion Light Maintenance Malignant Neoplasms Mediating Mitomycins Molecular Motor Motor Activity Mutagens Mutation Neurodegenerative Disorders Nuclear Nucleic Acids Null Lymphocytes Outcome Pathogenicity Pathway interactions Pharmacotherapy Play Process Proteins RNA Helicase Radiation Regulation Resistance Resolution Role Small Interfering RNA Stress Zinc Fingers base causal variant cell transformation cofactor environmental agent helicase homologous recombination insight mutant novel strategies prevent protein protein interaction repaired replication stress response stem telomere tool

项目摘要

PROJECT SUMMARY/ABSTRACT Exposure of cells to environmental agents, such as radiation, heavy metals, air pollutants and mutagenic chemicals, generates DNA double-strand breaks (DSB)s and other chromosomal lesions, and can also cause replicative stress. Such environmentally induced chromosomal lesions and stress are eliminated by a conserved mechanism - homologous recombination (HR). Defects in HR and its deregulation lead to genome destabilization, cancer, and other diseases. Several nucleic acid motor proteins, including helicases, have been implicated in mechanisms that affect HR outcome and DNA damage repair, relieve cells from replication fork stress, and mediate the resolution of R-loops. ZGRF1, a nucleic acid motor, has been implicated in HR and DNA crosslink repair in siRNA- based genomic screens. We have found that engineered ZGRF1-/- cells are hypersensitivity to mitomycin C (MMC) treatment and accumulate chromosome aberrations upon drug treatment. Importantly, purified ZGRF1 shows DNA dependent ATPase, D-loop and R-loop dissociation, and replication fork regression activities, suggesting that ZGRF1 functions directly to regulate HR and mediate replication fork repair and R-loop resolution. In this project, we will apply our considerable expertise in molecular studies of nucleic acid motor proteins to define the mechanisms by which ZGRF1 accomplishes its biological functions. In Aim 1, we will perform a variety of genetic and cytological studies to examine ZGRF1 mutant cells for defects in DNA damage repair, replication fork maintenance/repair, and also R-loop resolution. We will ascertain the biological relevance of the ZGRF1 nucleic acid motor activity with an ATPase defective mutant that we have generated. In Aim 2, we will define the biochemical attributes of ZGRF1, and carry out co- immunoprecipitation and biochemical pulldown to identify interactors of this motor protein. In Aim 3, we will investigate the biochemical and genetic defects of ZGRF1 mutants altered in the zinc finger domain, impaired for protein-protein interactions, or found in cancer. The results from our project will shed light on the roles of ZGRF1 in nuclear processes that are germane for delineating how disease causative mutations and chromosome rearrangements arise in cells deficient in nucleic acid motors. The results on R-loop resolution are expected to contribute toward the development of novel strategies to avoid the accumulation of R-loops upon exposure to environmental stress and mutagens.

项目总结/文摘