人体细胞衰老与端粒的稳定性和长度密切相关。端粒的合成由端粒酶非编码RNA TERC为模板, TERT亚基催化，其中TERC的3’加工机制还不清楚。申请人团队首次鉴定出定位于卡哈尔小体的早期生长应答因子靶蛋白TOE1能够结合端粒酶装配复合物，卡哈尔小体是TERC成熟和端粒酶装配之处。已有证据显示TOE1具脱腺苷酸酶活性，但体内底物特异性仍不清楚。我们假设，TOE1能否通过调控TERC的加工进而影响端粒酶活性？我们初步研究显示TOE1对维持端粒酶阳性细胞的端粒酶活性是必需的。TOE1的缺失下调端粒酶活性，降低成熟TERC的比例。本项目拟用分子细胞生物学、生物化学、蛋白质-RNA组学、高通量测序生物信息学分析等技术，利用端粒酶阳性的肿瘤细胞和其他细胞及临床样品为研究体系，系统阐明TOE1对端粒酶活性调控的生物学功能和影响TERC 3’加工的分子机制，为衰老相关疾病如恶性肿瘤提供新的机制和靶点。

The stability and length of telomere are closely related to human cell senescence. The telomerase is composed of catalytic TERT and non-coding RNA template TERC, responsible for telomere lengthening. The regulatory mechanisms of TERC 3’ processing remain largely unknown. For the first time our group identified a protein called TOE1 (Target of Early Growth Response 1) located in the Cajal Body which interacts with telomerase associated protein complex. Cajal Body is the place where TERC maturates and telomerase assembly. TOE1 was reported as a deadenylase while its target specificity was unclear yet. We hypothesized that TOE1 may regulate telomerase activity via TERC 3’ processing. Our preliminary data found TOE1 is required for the maintainance of telomerase activity in telomerase positive cells. Loss of TOE1 downregulates telomerase activity and decreases the ratio of mature TERC. We will use multiple techniques such as molecular cell biology, biochemistry, protein-RNA interaction genomics as well as high throughput sequencing and bioinformatics, to systemically illustrate the role of TOE1 in regulating telomerase activity as well as the detail molecular mechanism in modulating 3’ processing within the telomerase positive tumor cells and other cells, as well as within the clinical tumor samples. Our study will provide novel mechanism and target for the ageing related disorders such as tumor biogenesis.