TRANCRIPTION-COUPLED DNA REPAIR AND GENETIC INSTABILITY

许多环境和内生因素可以暂时绑定到 DNA靶标和抑制基因转录。这些因素是否会导致DNA 修复和定向突变在很大程度上还不清楚。在他们之前的研究中， 寡核苷酸三联体的形成已被证明具有 在SV40病毒载体中诱导定向突变。三链介导型 靶向突变已被进一步证明与DNA有关 核苷酸切除修复和转录偶联修复。由于三联体 在哺乳动物基因组DNA中被检测到，这一观察结果提高了 细胞内的三联体以及其他环境和 已知的暂时抑制基因转录的内源性因素可能具有 有可能诱发TCR并导致有针对性的突变；此外， TCR介导的靶向突变可能导致遗传不稳定和 导致许多人类疾病的发展，包括遗传病、癌症、 神经退行性疾病和衰老相关疾病。 王博士建议研究转录偶联的分子机制 修复及其转录偶联修复与遗传的相关性 以DNA三链结构为模型体系的不稳定性。三链介导型 转录偶联修复将在体外和体内使用 具有不同DNA修复背景的人类细胞。胞内三链 结构介导的遗传不稳定性将在SV40病毒中进行研究 系统和在人类细胞中携带着染色体内的lambda穿梭载体。 转录偶联修复与其他DNA修复的相关性 核苷酸切除修复和错配修复等途径也将被 使用不同的DNA修复熟练和缺陷的人类细胞进行研究。这个 从这个项目中获得的知识将提供对 转录偶联修复的分子机制及其在细胞周期调控中的作用 遗传不稳定。从这个项目中获得的知识也将导致 了解许多环境和内生因素是否已知 只有抑制基因转录才能诱导靶向突变并导致 基因的不稳定可能导致许多人类的发育 疾病包括遗传病、癌症、神经退行性疾病和 与衰老相关的疾病。从长远来看，对 转录偶联修复将具有重要的科学和临床意义 因为从这个项目中获得的知识不仅将有利于科学 转录调控和DNA修复/复制等研究，还包括 可能有助于预防许多由细胞内引起的人类疾病的发展 三重以及其他环境和内生因素。

Many environmental and endogenous factors can temporarily bind to DNA targets and inhibit gene transcription. Whether these factors induce DNA repair and targeted mutagenesis is largely unclear. In their previous studies, oligonucleotide triplex formation has been demonstrated to have the capability of inducing targeted mutagenesis in an SV40 viral vector. Triplex-mediated targeted mutagenesis has been further demonstrated to be related to DNA nucleotide excision repair and transcription-coupled repair. Since triplexes have been detected in mammalian genomic DNAs, this observation has raised the possibility that intracellular triplexes as well as other environmental and endogenous factors known to temporarily inhibit gene transcription may have the potential to induce TCR and cause targeted mutagenesis; furthermore, TCR-mediated targeted mutagenesis may contribute to genetic instability and lead to development of many human diseases including genetic diseases, cancer, neurodegenerative and aging-related diseases. Dr. Wang proposes to study the molecular mechanisms of transcription-coupled repair and the correlation between transcription-coupled repair and genetic instability using DNA triplex structure as a model system. Triplex-mediated transcription-coupled repair will be studied both in vitro and in vivo using human cells with different DNA repair background. Intracellular triplex structure-mediated genetic instability will be studied both in SV40 viral systems and in human cells carrying lambda shuttle vectors within chromosomes. The correlation between transcription-coupled repair and other DNA repair pathways such as nucleotide excision repair and mismatch repair also will be studied using different DNA repair-proficient and deficient human cells. The knowledge obtained from this project will provide an understanding of the molecular mechanisms of transcription-coupled repair and its contribution in genetic instability. The knowledge gained from this project also will lead to an understanding of whether many environmental and endogenous factors known only to inhibit gene transcription could induce targeted mutagenesis and result in genetic instability that might contribute to the development of many human diseases including genetic diseases, cancer, neurodegenerative and aging-related diseases. In long term, the understanding of transcription-coupled repair will have both scientific and clinical importance since the knowledge obtained from this project not only will benefit scientific research such as transcription regulation and DNA repair/replication but also may help to prevent development of many human diseases caused by intracellular triplexes and other environmental and endogenous factors.