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Mechanism of transcription-associated genome instability

转录相关基因组不稳定的机制

基本信息

批准号：
10474278
负责人：
Nayun Kim
金额：
$ 38.71万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10474278
关键词：
Address Adverse event Animal Model Binding Cell Cycle Cell physiology Cells Chromosomal Rearrangement Chromosomes Complex DNA DNA Damage DNA Repair DNA Structure DNA biosynthesis DNA-Binding Proteins DNA-Directed DNA Polymerase DNA-Directed RNA Polymerase Development Disease Event Frequencies G-Quartets G1 Phase G2 Phase Genes Genetic Recombination Genetic Transcription Genome Genomic Instability Goals In Vitro Investigation Knowledge Link Malignant Neoplasms Mission Modeling Mutagenesis Mutation Nucleosides Process Proteins Public Health Research Ribonucleotides Saccharomyces cerevisiae Stress Structure System Testing Topoisomerase Torsion Transcription Process Transcriptional Activation United States National Institutes of Health Uracil Work cancer therapy density genetic approach genome integrity grasp in vivo innovation metaplastic cell transformation novel programs protein complex response tumorigenesis

项目摘要

PROJECT SUMMARY: Changes in the genome such as mutagenesis, duplication, deletions, and recombination bring about somatic diseases like cancer and drive evolutionary processes. My lab has been focused on understanding how such genome instability events occur at incongruently higher frequencies at certain “hotspots.” Quite different from the familiar depiction of chromosomes as stationary strings made up of DNA, genome is more like a busy highway, where many proteins, including topoisomerases in surveillance for irregular helical torsion, bind and/or actively modify DNA. Moreover, mega-complexes of proteins like RNA polymerase and DNA polymerase complexes are dynamically moving along, unwinding, and forcibly distorting DNA while carrying out transcription and replication, sometimes physically colliding with each other. In order to explain why mutation/recombination hotspots are often located within actively transcribed regions, we viewed the multiple DNA-involving processes as an interactive system rather than as each independent activity and identified transcription-associated causes of genome instability. My work was instrumental in showing that mutations resulting from the non-canonical residues, uracil and ribonucleotide, are highly elevated upon transcription activation. Subsequently, novel discoveries in my lab led to the model that non-replicative DNA synthesis occurring in G1- and G2-phases of the cell cycles results in higher uracil density in actively transcribed genes. We also made key findings linking the transcription-generated negative torsional stress with the elevated recombination associated with the DNA secondary structure G-quadruplex or G4 DNA. We further identified G4 DNA-binding proteins that either suppress or exacerbate such G4 DNA-induced genome instability. The central goal of my research program is to uncover fundamental and conserved mechanism underlying mutagenesis and genome rearrangements, which will be important for both the cellular transformation into cancers and responses to chemotherapeutics. Building upon our previous findings, we will continue to address important remaining questions by (1) using tractable genetic approaches to study transcription-associated genome instability in the simple eukaryotic model organism Saccharomyces cerevisiae, (2) developing innovative approaches to test the model of uracil/ribonucleotide incorporation into DNA during G1 and G2, and (3) defining the functional and structural interaction between key G4 DNA-binding proteins and G4 DNA both in vitro and in vivo. Our ongoing investigation should further the understanding of how transcription, replication, and DNA repair work in conjunction either for the benefit or the detriment of genome integrity. Having a comprehensive picture of these interconnected and dynamic processes occurring on the genome will help in predicting how to suppress and correct genome instability events adverse to normal cellular functions.

项目概述：基因组的变化，如突变、重复、缺失和