Molecular Dissection of Telomeric Repeat-Containing RNA Biogenesis Unveils the Presence of Distinct and Multiple Regulatory Pathways
Molecular Dissection of Telomeric Repeat-Containing RNA Biogenesis Unveils the Presence of Distinct and Multiple Regulatory Pathways
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DOI：
10.1128/mcb.00460-10
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发表时间：
2010-10-10
影响因子：
5.3
通讯作者：
Lingner, Joachim
中科院分区：
文献类型：
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作者：
Porro, Antonio;Feuerhahn, Sascha;Lingner, Joachim
端粒被转录成含有端粒重复序列的RNA(Terra)，这是一种大的、异质的、非编码的转录本，构成了端粒异染色质的一部分。尽管有大量的功能被归因于Terra，但人们对它的生物起源知之甚少。在这里，我们首次对Terra的分子结构进行了全面的分析。我们确定了不同的生物化学Terra复合体，并描述了Terra在细胞周期中的调节。此外，我们证明了Terra 5‘端含有7-甲基鸟苷帽结构，并且在Terra转录本的一小部分上存在的聚(A)尾巴有助于它们的稳定性。Poly(A)(-)Terra与染色质有关，但与Poly(A)(+)Terra无关，这可能反映了Terra核糖核蛋白复合体的不同生物学作用。为了支持这一观点，聚(A)(-)和聚(A)(+)Terra分子以不同的序列寄存器结束。我们还确定了TERRA的3‘-末端UUAGGG重复序列的平均长度为200个碱基，这表明Terra的长度不均一性可能源于其亚端粒区域。最后，我们发现Terra在细胞周期中受到调控，在S晚期最低，在G(1)期早期达到高峰。我们的分析为研究影响Terra合成、加工、周转和功能的多种调控途径提供了基础。
Telomeres are transcribed into telomeric repeat-containing RNA (TERRA), large, heterogeneous, non-coding transcripts which form part of the telomeric heterochromatin. Despite a large number of functions that have been ascribed to TERRA, little is known about its biogenesis. Here, we present the first comprehensive analysis of the molecular structure of TERRA. We identify biochemically distinct TERRA complexes, and we describe TERRA regulation during the cell cycle. Moreover, we demonstrate that TERRA 5' ends contain 7-methylguanosine cap structures and that the poly(A) tail, present on a fraction of TERRA transcripts, contributes to their stability. Poly(A)(-) TERRA, but not poly(A)(+) TERRA, is associated with chromatin, possibly reflecting distinct biological roles of TERRA ribonucleoprotein complexes. In support of this idea, poly(A)(-) and poly(A)(+) TERRA molecules end with distinct sequence registers. We also determine that the bulk of 3' -terminal UUAGGG repeats have an average length of 200 bases, indicating that the length heterogeneity of TERRA likely stems from its subtelomeric regions. Finally, we find that TERRA is regulated during the cell cycle, being lowest in late S phase and peaking in early G(1). Our analyses offer the basis for investigating multiple regulatory pathways that affect TERRA synthesis, processing, turnover, and function.