老年性疾病和器官功能退化与细胞衰老有关。传统观念认为端粒复制损伤促进细胞衰老。我们发现端粒参与染色质重组激活DNA损伤（DDR）可能是端粒调控衰老的新机制。我们前期研究证明端粒保护蛋白TRF2为中心的多酶体系抑制DDR，确保端粒复制完整和预防衰老；Chip-Seq分析TRF2能结合至去磷酸化酶PPP2R2C启动子区的间质性端粒（ITS）。本课题将⑴使用Chip等方法证明细胞衰老致TRF2从端粒解离并招募至ITS；⑵报告基因体系等证明TRF2结合ITS反式调控PPP2R2C转录；⑶基因毒性衰老模型证明PPP2R2C能修饰DDR重要蛋白H2AX磷酸化；基因静默等证明TRF2调控PPP2R2C表达的作用为操纵DDR，启动衰老。该研究将探索并阐明环境等致TRF2在端粒和ITS的长距离染色质互动，通过染色质重组激活DDR，是除复制损伤以外的端粒调控衰老的又一新机制，为老年性疾病预防和治疗提供新思路。

Cellular senescence induces tissue degeneration and aging syndrome. Telomere dysfunction activates DNA Damage Response (DDR) and leads to senescence. Our previous paper has shown that Telomeric Repetitive Factor 2 (TRF2) as a core protein of multi-enzyme complexes at telomeres can protect telomere during replication by inhibiting DDR machinery. This revealed the mechanism of TRF2 in preventing aging. In this project, we will explore the mechanism of TRF2 and Interstitial Telomeric Sequence (ITS) in the chromatin reprogramming of DDR activation. Our high-throughput Chip-Sequence analysis has shown that TRF2 binds to the ITS at the promoter region of phosphorylase PPP2R2C. We will use (1) Chip assay to verify our proposal that cellular senescence will induce the dissociation of TRF2 from telomeres and recruit it to the ITS; (2) reporter gene system and protein system to show that TRF2 binds to the ITS and induces the trans-regulation of PPP2R2C transcription; (3) genotoxic reagents induced senescence model to show PPP2R2C can phosphorylate H2AX, a crucial sensor protein of DDR system. Our primary experiments have shown that gene silencing of PPP2R2C, followed by RT-PCR and IF assay indicate that TRF2 may control DDR activation and initiate senescence by regulating PPP2R2C expression. Different from the concept of replicative senescence, the novel proposal of DDR induced senescence are due to the cellular micro-environmental changes, which induce the equilibrium of TRF2 expression between telomeres and ITS. TRF2 binding at ITS will participate in the chromatin reorganization and activation of DDR, and finally mediate senescence. This project will contribute to the screening of senescence markers, prevention of organ fibrosis and the treatment of degenerative diseases.