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

Repair of Genome Destabilizing DNA Structures

修复基因组不稳定的 DNA 结构

基本信息

批准号：
7897165
负责人：
Karen M Vasquez
金额：
$ 29.48万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-01-28 至 2011-02-25
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7897165
关键词：
B-DNA Binding Biological Assay Cell Line Cell Survival Cells Chemotherapy-Oncologic Procedure Chromosome Breakage Chromosomes DNA DNA Damage DNA Double Strand Break DNA Fingerprinting DNA Repair DNA Sequence DNA Structure DNA biosynthesis DNA lesion DNA repair protein Development Disease Endogenous Factors Environment Ficusin Frequencies Funding Generations Genes Genetic Genetic Transcription Genome Genome Stability Genomic Instability Goals H-DNA Health Human Human Cell Line Lead Lesion Life Lymphoma MSH2 gene Maintenance Malignant Neoplasms Mammalian Cell Maps Measures Mismatch Repair Modeling Molecular Mus Mutagenesis Mutation Nucleotide Excision Repair Oligonucleotides Oncogenic Organism Pathogenesis Pathologic Mutagenesis Plasmids Play Prevention Process Proteins Psoralens Replication Origin Reporter Research Personnel Role SV40 T Antigens Screening procedure Shuttle Vectors Signal Transduction Simian virus 40 Site Structure System Testing Transgenic Mice Transgenic Organisms Translocation Breakpoint Work Z-Form DNA base cancer cell carcinogenesis chemotherapy crosslink endonuclease human DNA insight leukemia/lymphoma molecular recognition novel novel strategies prevent programs promoter repaired research study xeroderma pigmentosum group A complementing protein

项目摘要

DNA damage and repair are fundamental to human health and disease. The long-term objectives of this application are to: expand our understanding of the role of DNA helical distortions in DNA damage recognition and processing; determine the factors influencing DNA structure-induced genetic instability; elucidate potential mechanisms involved in translocations associated with certain cancers; and further the development of novel approaches to reduce genetic instability in human cells. In the short term, we will pursue our recent discovery that helical distortions induced by naturally occurring Z-DNA and H-DNA structures are highly mutagenic and can induce DNA double-strand breaks (DSBs) in mammalian cells. We propose to study the effect of DNA helical distortions on genomic instability in plasmid-based systems as well as on chromosomes in human cells and in transgenic mutation-reporter mice. We will focus on the H- DNA-forming sequence located near the translocation breakpoint in the human c-MYC promoter and the Z- DNA sequence located at a chromosomal breakpoint in the human BCL-2 gene, found in lymphomas and leukemias. We will determine the role(s) of DNA repair, replication and transcription in the structure-induced genetic instability. We will use our expertise in the introduction of site-specific DNA helical distortions in the form of well-defined intermolecular triplex structures to test our hypothesis that certain types of DNA helical distortions (in the presence or absence of DNA damage per se) are recognized by the DNA repair machinery in human cells. The new information obtained from these studies will provide insight into the mechanisms of non-B DNA-induced genetic instability; the rate-limiting step in human DNA repair (i.e.distortion/damage recognition); and the overlap between nucleotide excision repair and mismatch repair in processing DNA helical distortions. It will also identify the proteins involved in the generation of DSBs induced bynon- canonical DNA structures formed at sequences that map to translocation breakpoints in human cancers. These discoveries should lead to a better understanding of the pathogenesis of cancers and other diseases that are caused by DNA damage and naturally occurring helical distortions, and ultimately to the development of new approaches to treatment and prevention.

DNA的损伤和修复是人类健康和疾病的基础。这方面的长期目标