MLL Associates with Telomeres and Regulates Telomeric Repeat-Containing RNA Transcription
MLL Associates with Telomeres and Regulates Telomeric Repeat-Containing RNA Transcription
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DOI：
10.1128/mcb.00195-09
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发表时间：
2009-08-15
影响因子：
5.3
通讯作者：
Hess, Jay L.
中科院分区：
文献类型：
--
作者：
Caslini, Corrado;Connelly, James A.;Hess, Jay L.
哺乳动物端粒由TTAGGG重复序列组成，该重复序列在核小体中组织并与称为shelterin的六蛋白复合物相关，该复合物保留端粒结构并保护染色体末端免受细胞DNA损伤反应。最近的研究发现，端粒转录成端粒UUAGGG重复序列的RNA（TERRA）从亚端粒区域开始。TERRA在端粒的结合似乎参与了端粒染色质组织和维持的顺式机制。已知许多组蛋白甲基转移酶（HMT）影响端粒染色质状态;然而，对端粒转录的调控机制知之甚少。在这里，我们表明，组蛋白3/赖氨酸4（H3/K4）HMT和转录调节MLL与端粒，并有助于其H3/K4甲基化和转录端粒长度依赖性的方式。在人二倍体成纤维细胞中，RNA干扰介导的MLL耗竭影响端粒染色质修饰和转录，并诱导端粒损伤反应。通过TRF 2 shelterin蛋白敲低或暴露于端粒G-链DNA寡核苷酸的端粒去帽化显著增加TERRA的转录，这是MLL和肿瘤抑制因子p53之间的功能合作介导的效应。总之，我们的研究结果确定了以前未被认识到的作用MLL在修改端粒染色质，并提供证据MLL，p53，和shelterin复杂的调节端粒转录和稳定性之间的功能相互作用。
Mammalian telomeres consist of TTAGGG repeats organized in nucleosomes and associated with a six-protein complex known as shelterin, which preserves telomere structure and protects chromosome ends from the cellular DNA damage response. Recent studies have found that telomeres are transcribed into telomeric UUAGGG repeat-containing RNA (TERRA) starting from subtelomeric regions. TERRA binding at telomeres appears to be involved in cis-based mechanisms of telomeric chromatin organization and maintenance. A number of histone methyltransferases (HMTs) are known to influence telomeric chromatin status; however, the regulatory mechanisms of telomere transcription are poorly understood. Here, we show that the histone 3/lysine 4 (H3/K4) HMT and the transcriptional regulator MLL associate with telomeres and contribute to their H3/K4 methylation and transcription in a telomere length-dependent manner. In human diploid fibroblasts, RNA interference-mediated MLL depletion affects telomere chromatin modification and transcription and induces the telomere damage response. Telomere uncapping through either TRF2 shelterin protein knockdown or exposure to telomere G-strand DNA oligonucleotides significantly increases the transcription of TERRA, an effect mediated by the functional cooperation between MLL and the tumor suppressor p53. In total, our findings identify a previously unrecognized role of MLL in modifying telomeric chromatin and provide evidence for the functional interaction between MLL, p53, and the shelterin complex in the regulation of telomeric transcription and stability.