Tethering telomerase to telomeres increases genome instability and promotes chronological aging in yeast.
Tethering telomerase to telomeres increases genome instability and promotes chronological aging in yeast.
复制标题
将端粒酶束缚在端粒上会增加基因组的不稳定性并促进酵母的老化。
DOI：
10.18632/aging.101095
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发表时间：
2016-11-13
期刊：
影响因子：
--
通讯作者：
Zhou JQ
中科院分区：
文献类型：
--
作者：
Liu J;He MH;Peng J;Duan YM;Lu YS;Wu Z;Gong T;Li HT;Zhou JQ
酵母的时间衰老归因于多方面的特征，特别是那些涉及基因组不稳定性的特征，并且被认为是高等生物有丝分裂后细胞的衰老模型。端粒是真核生物染色体的物理末端，对基因组的完整性和稳定性至关重要。端粒酶活性失调是否影响时间顺序衰老仍是一个谜。我们使用CDC13-EST2融合基因，将端粒酶连接到端粒，来检测组成活性端粒酶对时间顺序寿命（CLS）的影响。Cdc13-Est2融合蛋白的表达导致端粒过长（比正常端粒长2 ~ 4倍），且长端粒在长期时间衰老过程中稳定维持。因此，基因组不稳定性显著升高，表现为染色体外rDNA环种的积累、年龄依赖性CAN1标记基因突变频率和染色体重排频率。重要的是，雷帕霉素复合物1靶点（TORC1）的下游激酶Sch9的失活抑制了CDC13-EST2表达介导的基因组不稳定性和加速时间衰老。有趣的是，端粒过长细胞中CDC13-EST2融合基因的缺失恢复了正常的CLS。总之，这些数据表明，组成活性端粒酶不利于维持基因组的稳定性，并促进酵母的时间衰老。
Chronological aging of the yeast Saccharomyces cerevisiae is attributed to multi-faceted traits especially those involving genome instability, and has been considered to be an aging model for post-mitotic cells in higher organisms. Telomeres are the physical ends of eukaryotic chromosomes, and are essential for genome integrity and stability. It remains elusive whether dysregulated telomerase activity affects chronological aging. We employed the CDC13-EST2 fusion gene, which tethers telomerase to telomeres, to examine the effect of constitutively active telomerase on chronological lifespan (CLS). The expression of Cdc13-Est2 fusion protein resulted in overlong telomeres (2 to 4 folds longer than normal telomeres), and long telomeres were stably maintained during long-term chronological aging. Accordingly, genome instability, manifested by accumulation of extra-chromosomal rDNA circle species, age-dependent CAN1 marker-gene mutation frequency and gross chromosomal rearrangement frequency, was significantly elevated. Importantly, inactivation of Sch9, a downstream kinase of the target of rapamycin complex 1 (TORC1), suppressed both the genome instability and accelerated chronological aging mediated by CDC13-EST2 expression. Interestingly, loss of the CDC13-EST2 fusion gene in the cells with overlong telomeres restored the regular CLS. Altogether, these data suggest that constitutively active telomerase is detrimental to the maintenance of genome stability, and promotes chronological aging in yeast.
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影响因子：
7.8
作者：
Bernardes de Jesus B;Schneeberger K;Vera E;Tejera A;Harley CB;Blasco MA
通讯作者：
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影响因子：
56.9
作者：
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通讯作者：
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DOI：
10.1073/pnas.94.18.9768
发表时间：
1997-09-02
影响因子：
11.1
作者：
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通讯作者：
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56.9
作者：
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VILLEPONTEAU, B
影响因子：
4.5
作者：
Huang X;Liu J;Dickson RC
通讯作者：
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