Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Frontiers in Genetics National Center of Competence in Research, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
PLoS Genet. 2012;8(6):e1002747. doi: 10.1371/journal.pgen.1002747. Epub 2012 Jun 14.
The long noncoding telomeric repeat containing RNA (TERRA) is expressed at chromosome ends. TERRA upregulation upon experimental manipulation or in ICF (immunodeficiency, centromeric instability, facial anomalies) patients correlates with short telomeres. To study the mechanism of telomere length control by TERRA in Saccharomyces cerevisiae, we mapped the transcriptional start site of TERRA at telomere 1L and inserted a doxycycline regulatable promoter upstream. Induction of TERRA transcription led to telomere shortening of 1L but not of other chromosome ends. TERRA interacts with the Exo1-inhibiting Ku70/80 complex, and deletion of EXO1 but not MRE11 fully suppressed the TERRA-mediated short telomere phenotype in presence and absence of telomerase. Thus TERRA transcription facilitates the 5'-3' nuclease activity of Exo1 at chromosome ends, providing a means to regulate the telomere shortening rate. Thereby, telomere transcription can regulate cellular lifespan through modulation of chromosome end processing activities.
长非编码端粒重复 RNA（TERRA）在染色体末端表达。实验操作或 ICF（免疫缺陷、着丝粒不稳定、面异常）患者中 TERRA 的上调与短端粒相关。为了研究 TERRA 在酿酒酵母中端粒长度控制的机制，我们在端粒 1L 上绘制了 TERRA 的转录起始位点，并在上游插入了一个强力霉素可调节的启动子。TERRA 转录的诱导导致 1L 端粒缩短，但其他染色体末端没有缩短。TERRA 与抑制 Exo1 的 Ku70/80 复合物相互作用，并且 EXO1 的缺失而不是 MRE11 的缺失完全抑制了端粒酶存在和不存在时 TERRA 介导的短端粒表型。因此，TERRA 转录促进了 Exo1 在染色体末端的 5'-3'核酸酶活性，提供了一种调节端粒缩短率的方法。因此，端粒转录可以通过调节染色体末端处理活性来调节细胞寿命。
