Porro Antonio, Feuerhahn Sascha, Delafontaine Julien, Riethman Harold, Rougemont Jacques, Lingner Joachim
1] Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland [2] Swiss Institute for Experimental Cancer Research (ISREC) at EPFL, Station 19, CH-1015 Lausanne, Switzerland.
1] Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland [2] Bioinformatics and Biostatistics Core Facility, EPFL and Swiss Institute of Bioinformatics, Station 15, CH-1015 Lausanne, Switzerland.
Nat Commun. 2014 Oct 31;5:5379. doi: 10.1038/ncomms6379.
Telomere deprotection occurs during tumorigenesis and aging upon telomere shortening or loss of the telomeric shelterin component TRF2. Deprotected telomeres undergo changes in chromatin structure and elicit a DNA damage response (DDR) that leads to cellular senescence. The telomeric long noncoding RNA TERRA has been implicated in modulating the structure and processing of deprotected telomeres. Here, we characterize the human TERRA transcriptome at normal and TRF2-depleted telomeres and demonstrate that TERRA upregulation is occurring upon depletion of TRF2 at all transcribed telomeres. TRF2 represses TERRA transcription through its homodimerization domain, which was previously shown to induce chromatin compaction and to prevent the early steps of DDR activation. We show that TERRA associates with SUV39H1 H3K9 histone methyltransferase, which promotes accumulation of H3K9me3 at damaged telomeres and end-to-end fusions. Altogether our data elucidate the TERRA landscape and defines critical roles for this RNA in the telomeric DNA damage response.
在肿瘤发生和衰老过程中，当端粒缩短或端粒保护蛋白复合物TRF2缺失时，端粒保护作用丧失。去保护的端粒会发生染色质结构变化，并引发DNA损伤反应（DDR），进而导致细胞衰老。端粒长链非编码RNA TERRA被认为参与调节去保护端粒的结构和加工过程。在此，我们对正常端粒和TRF2缺失的端粒处的人类TERRA转录组进行了表征，并证明在所有转录的端粒处，TRF2缺失时TERRA表达上调。TRF2通过其同源二聚化结构域抑制TERRA转录，该结构域先前已被证明可诱导染色质压缩并阻止DDR激活的早期步骤。我们发现TERRA与SUV39H1 H3K9组蛋白甲基转移酶相关联，后者促进H3K9me3在受损端粒处的积累以及端粒间的融合。我们的数据共同阐明了TERRA的全貌，并确定了这种RNA在端粒DNA损伤反应中的关键作用。
