TRF2 recruits nucleolar protein TCOF1 to coordinate telomere transcription and replication
TRF2 recruits nucleolar protein TCOF1 to coordinate telomere transcription and replication
复制标题
TRF2招募核仁蛋白TCOF1来协调端粒转录和复制
DOI：
10.1038/s41418-020-00637-3
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发表时间：
2020-10-20
影响因子：
12.4
通讯作者：
Zhao, Yong
中科院分区：
文献类型：
--
作者：
Nie, Xin;Xiao, Danqing;Zhao, Yong
端粒被转录成端粒RNA，称为Terra。然而，转录本身和过量的Terra可能会干扰S期的端粒复制。协调端粒转录和复制的机制尚不清楚。在这里，我们报道了TCOF1离开核仁，并通过与TRF2相互作用，在S时期特异性地被招募到端粒。其中，TCOF1通过结合和抑制Pol II来抑制端粒转录。因此，Terra仅限于S期的低水平。TCOF1的缺失导致Terra的异常升高和端粒DNA/RNA杂交体(R-环)的形成，从而导致复制分叉停滞和脆弱的端粒。重要的是，TCOF1缺乏引起的端粒复制缺陷可以通过掩蔽Terra或表达R-loop擦除器RNase-H1来挽救，这表明TCOF1在协调端粒转录和复制方面发挥了关键作用。这些发现将核仁与端粒联系起来，并揭示了TCOF1在确保端粒完整性方面的一项新功能。
Telomeres are transcribed into telomeric RNA termed as TERRA. However, the transcription itself and excessive TERRA may interfere with telomere replication during S phase. The mechanism that coordinates telomere transcription and replication is unknown. Here, we report that TCOF1 leaves the nucleolus and is recruited to telomeres specifically during S phase by interacting with TRF2. Therein, TCOF1 acts to suppress telomere transcription by binding and inhibiting Pol II. Thus, TERRA is limited to low levels in S phase. Depletion of TCOF1 leads to abnormally elevated TERRA and formation of DNA/RNA hybrids (R-loops) at telomeres, which induces replication fork stalling and fragile telomeres. Importantly, telomere replication defect induced by TCOF1 deficiency can be rescued by either masking TERRA or expressing an R-loop eraser RNase H1, demonstrating a critical role of TCOF1 in coordinating telomere transcription and replication. These findings link nucleolus to telomeres and uncover a novel function of TCOF1 on ensuring telomere integrity.