TRF2 recruits nucleolar protein TCOF1 to coordinate telomere transcription and replication

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.