端粒位于染色体末端，对于维护染色体结构和功能的稳定性具有重要作用。端粒由重复的序列组成，是典型的“脆性位点（Fragile site）”，面临复制困难。另外，端粒可以被转录，生成端粒RNA(TERRA)。在S期，端粒转录与复制发生冲突，导致端粒复制障碍，诱发染色体不稳定性，最终引起细胞衰老或凋亡。本项目将研究细胞解决端粒转录与复制冲突的分子机制。我们前期研究结果表明：核仁蛋白TCOF1在S期定位到端粒上，具有抑制端粒转录，促进端粒复制的功能。基于此，本课题将利用细胞、小鼠模型系统研究TCOF1协调端粒转录与复制的分子机制，包括TCOF1蛋白的转运与定位、与端粒的相互作用、调控端粒转录的分子机制以及TCOF1缺失对端粒复制、染色体稳定性、细胞衰老的影响。研究将揭示核仁与端粒的关系，并探究端粒复制障碍引起的细胞衰老与Treacher Collins 综合征发生（TCOF1突变引起）的关系。

Telomeres located at the end of chromosomes play an essential role in maintaining stability of genome structure and function. Human telomeres are composed of tandem repeats of short DNA sequences. As a typical fragile site, telomeres bear high loads of replication stress. In addition, telomeres are transcribed into long non-coding RNA known as TERRA (telomeric repeat-containing RNA). Telomere transcription during S phase may conflict with its replication, leading to telomere replication defect, which could result in genome instability, cell senescence or apoptosis. Proposed project will study molecular mechanisms for resolving the conflict between telomere transcription and replication. Our preliminary data showed that nucleolar protein TCOF1 is specifically localized to telomeres during S phase of cell cycle and that TCOF1 play an important role in suppressing telomere transcription and promoting telomere replication. Based on these findings, we proposed to investigate the mechanism underlying the coordination between telomere transcription and replication during S phase, including transportation and localization of TCOF1, the interaction of TCOF1 with telomeres, the regulatory mechanism of telomere transcription by TCOF1 and impact of TCOF1 deficiency on telomere replication, chromosome stability and cell senescence. These studies would not only reveal the relationship between nucleolus and telomeres, but also elucidate how telomere replication defect and thus resulted cell senescence are involved in pathogenesis of Treacher Collins syndrome induced by genetic mutation in TCOF1 .