Telomeric RNA-DNA hybrids affect telomere-length dynamics and senescence
Telomeric RNA-DNA hybrids affect telomere-length dynamics and senescence
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DOI：
10.1038/nsmb.2662
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发表时间：
2013-10-01
影响因子：
16.8
通讯作者：
Luke, Brian
中科院分区：
文献类型：
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作者：
Balk, Bettina;Maicher, Andre;Luke, Brian
虽然端粒是异染色质的，但它们被转录成含有非编码端粒重复序列的RNA（TERRA）。在这里，我们表明，RNA-DNA杂交体在端粒处形成，并在出芽酵母（酿酒酵母）中被RNase H酶去除。在有重组能力的端粒酶突变体中，端粒RNA-DNA杂交促进重组介导的延长事件，延迟细胞衰老的发生。TERRA和端粒RNA-DNA杂交水平的降低降低了顺式重组介导的端粒延长的速率。RNase H的过表达会降低端粒重组率并加速有重组能力但不加速重组缺陷细胞的衰老。相反，在端粒酶和同源重组都不存在的情况下，端粒RNA-DNA杂合体的积累导致端粒损失和细胞衰老的加速速率。因此，TERRA转录和端粒RNA-DNA杂交形成的调节是端粒酶失活后端粒长度动态和增殖潜力的重要决定因素。
Although telomeres are heterochromatic, they are transcribed into noncoding telomeric repeat-containing RNA (TERRA). Here we show that RNA-DNA hybrids form at telomeres and are removed by RNase H enzymes in the budding yeast, Saccharomyces cerevisiae. In recombination-competent telomerase mutants, telomeric RNA-DNA hybrids promote recombination-mediated elongation events that delay the onset of cellular senescence. Reduction of TERRA and telomeric RNA-DNA-hybrid levels diminishes rates of recombination-mediated telomere elongation in cis. Overexpression of RNase H decreases telomere recombination rates and accelerates senescence in recombination-competent but not recombination-deficient cells. In contrast, in the absence of both telomerase and homologous recombination, accumulation of telomeric RNA-DNA hybrids leads to telomere loss and accelerated rates of cellular senescence. Therefore, the regulation of TERRA transcription and telomeric RNA-DNA-hybrid formation are important determinants of both telomere-length dynamics and proliferative potential after the inactivation of telomerase.