TRANCRIPTION-COUPLED DNA REPAIR AND GENETIC INSTABILITY

许多环境和内源性因素可以暂时结合到 DNA靶向并抑制基因转录。这些因素是否会诱导DNA 修复和靶向诱变在很大程度上是不清楚的。在他们之前的研究中， 已经证明寡核苷酸三链体形成具有 在SV 40病毒载体中诱导靶向诱变。三联体介导 已经进一步证明了定向诱变与DNA有关 核苷酸切除修复和转录偶联修复。由于三重 已经在哺乳动物基因组DNA中检测到，这一观察已经提出了 细胞内三链体以及其他环境和 已知暂时抑制基因转录的内源性因子可能具有 诱导TCR并引起靶向诱变的潜力;此外， TCR介导的靶向诱变可能导致遗传不稳定性， 导致许多人类疾病的发展，包括遗传疾病、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， 修复以及转录偶联修复与遗传 使用DNA三链体结构作为模型系统的不稳定性。三联体介导 转录偶联修复将在体外和体内进行研究， 不同的DNA修复背景的人类细胞。胞内三联体 结构介导的遗传不稳定性将在SV 40病毒 系统和在染色体内携带λ穿梭载体的人细胞中。 转录偶联修复与其他DNA修复的相关性 诸如核苷酸切除修复和错配修复的途径也将被 研究使用不同的DNA修复熟练和缺陷的人类细胞。的 从该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 遗传不稳定性从这个项目中获得的知识也将导致 了解是否有许多已知的环境和内源性因素 只有抑制基因转录才能诱导靶向突变并产生结果 基因的不稳定性，可能有助于许多人类的发展， 疾病，包括遗传疾病、癌症、神经退行性疾病和 与衰老有关的疾病。从长远来看， 转录偶联修复将具有科学和临床意义 因为从这个项目中获得的知识不仅有利于科学研究， 研究，如转录调控和DNA修复/复制，而且 可能有助于防止许多人类疾病的发展， 三链体和其他环境和内源性因素。

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.