基因组水平上DNA复制对核苷酸切除修复的影响研究

核苷酸切除修复是人类唯一能修复紫外损伤等DNA加合物损伤的途径，而DNA加合物损伤可以干扰DNA复制与转录、引起碱基突变，最终诱发皮肤癌等癌症。细胞内的核苷酸切除修复会受到基因组上染色质状态、DNA转录与复制等因素的影响。为了研究这些因素的影响，申请人建立了准确检测基因组上损伤和修复发生位置的高通量测序方法，揭示了基因组水平上染色质状态和转录等因素对损伤形成和修复的影响。然而，尽管DNA复制与DNA加合物损伤导致突变的过程紧密相关，但由于DNA复制是基因组上全局、动态的事件，它对附近区域核苷酸切除修复的影响目前尚不清楚。为了回答这个问题，本研究将检测处于复制早期和晚期的细胞中紫外损伤和修复的分布，结合DNA复制顺序数据以及其它基因组学数据，分析基因组上正在复制的区域附近的损伤修复。本项目的实施，预期将揭示DNA复制对核苷酸切除修复的影响，为癌症基因组中突变的来源提供新的见解。

Nucleotide excision repair is the sole mechanism to remove DNA bulky adducts like UV-induced lesions in humans. Bulky adducts can interfere with DNA replication and transcription, cause mutation and finally result in skin and other cancers. Cellular nucleotide excision repair may be affected by many factors such as chromatin structure, transcription and DNA replication. To investigate the influence of these factors, the applicant has developed two high-throughput sequencing-based methods to map the precise position of bulky adducts and their repair in the whole human genome and revealed how damage formation and repair are affected by chromatin structure, transcription and other factors. Furthermore, although DNA replication is tightly related to bulky adduct-induced mutagenesis, it is still unclear how DNA replication affect nearby nucleotide excision repair, because DNA replication is a global and dynamic event in the whole genome. In order to answer this question, this study will examine the distribution of UV-induced damage and their repair in cells of both early-S and late-S phases. In combination with DNA replication-timing data and other genomic data sets, we will analyze the genome-wide effect of DNA replication on local DNA repair. This project aims to unveil how DNA replication affect nearby nucleotide excision repair and improve our understanding of the mutagenesis of cancer genome.