Mechanisms of Trinucleotide Repeat Expansion via Oxidative DNA Damage and Repair

通过氧化 DNA 损伤和修复进行三核苷酸重复扩增的机制

• 批准号: 8137897
• 负责人: Yuan Liu
• 金额: $ 24.9万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-03 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8137897
• 关键词: 5' -deoxyribose phosphate lyase; Area; Award; Base Excision Repairs; Biochemical; Biochemistry; Bloom syndrome protein; CAG repeat; Chromates; Coenzymes; Complex; DNA; DNA Ligases; DNA Repair; DNA Single Strand Break; DNA ligase I; DNA strand break; DNA-(apurinic or apyrimidinic site) lyase; DNA-Directed DNA Polymerase; Degenerative Disorder; Deoxyribose; Development; Diagnosis; Disease; Ensure; Environmental Carcinogens; Etiology; Excision; Exposure to; Future; Goals; Guanine; HMGB1 Protein; Human; In Vitro; Intention; Knowledge; Lead; Malignant Neoplasms; Mediating; Mentors; Nerve Degeneration; Neurodegenerative Disorders; Nucleotides; Pathway interactions; Phase; Poly(ADP-ribose) Polymerases; Prevention; Process; Proliferating Cell Nuclear Antigen; Protein Biochemistry; Proteins; RTH-1 Nuclease; Research; Role; Series; Stress; Structure; Surgical Flaps; Testing; Trinucleotide Repeat Expansion; Trinucleotide Repeats; Work; X-Ray Cross Complementing Group; base; carcinogenesis; career; cofactor; design; human disease; ilium; in vivo; inorganic phosphate; insight; oxidation; oxidative DNA damage; prevent; protein protein interaction; repair enzyme; repaired; skills

My intention in obtaining ttie K99/R00 award is to extend my research into studies of in vivo interplay between DNA repeat sequence instability, DNA damage and repair in the field of human disease-associated repeat sequence instability that is induced by environmental stress and mediated by base excision repair (BER). IVIy long-term goal is to understand how exposure to environmental stress influences the development and progression of human diseases through initiating and modulating repeat sequence instability and how the environmentallv-induced effects can be prevented by DNA damage repair. I hypothesize that environmental oxidative DNA damage and its inefficient BER is involved in CAG repeat expansion. The hypothesis will be explored by two Specific Aims. Aim one is to determine how inefficient processing of oxidative single-strand DNA (ssDNA) break intermediates induced by environmental carcinogens, chromate and bromate may be involved in CAG repeat expansion. The impact of insufficient processing of ssDNA breaks on CAG repeat expansion will be determined under deficiency of Pol p dRP lyase and FEN1 cleavage of hairpin structures. Aim two is to determine if highly efficient processing of oxidative ssDNA breaks can prevent CAG repeat expansion. This aim will be examined by determining if CAG repeat expansion can be reduced by efficient processing of ssDNA break intermediates through BER protein interactions between APE1 and Pol p, XRCC1 and Pol 3, as well as BLM and FEN1. Under Dr. Wilson's mentoring, I have successfully accomplished my research and career goals during the mentored phase of the award period. I have established several approaches for analyzing CAG repeat instability in vivo and in vitro. This has advanced my skills and knowledge in analyzing in vivo TNR stability and BER biochemistry. This also consolidated the basis for fulfillment of research goals during the independent phase as well as construction of my future R01 proposals. My future research will emphasize work in the areas of cellular and biochemical studies on repeat sequence instability induced by environmental oxidative DNA damage. BER mutational effects on trinucleotide repeat stability and BER protein biochemistry.

我获得K99/R00奖的目的是将我的研究扩展到DNA重复序列不稳定性与DNA损伤和修复之间的体内相互作用的研究，在人类疾病相关的重复序列不稳定性领域，这种重复序列不稳定性是由环境应激诱导并由碱基切除修复（BER）介导的。IVIy的长期目标是了解暴露于环境压力如何通过启动和调节重复序列不稳定性来影响人类疾病的发展和进展，以及如何通过DNA损伤修复来预防环境诱导的影响。笔者推测环境DNA氧化损伤及其低效率BER参与了CAG重复