The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; UCL Genetics Institute, University College London, Gower Street, London WC1E 6BT, UK.
Cell Rep. 2020 Dec 22;33(12):108546. doi: 10.1016/j.celrep.2020.108546.
Regulator of telomere length 1 (RTEL1) is an essential helicase that maintains telomere integrity and facilitates DNA replication. The source of replication stress in Rtel1-deficient cells remains unclear. Here, we report that loss of RTEL1 confers extensive transcriptional changes independent of its roles at telomeres. The majority of affected genes in Rtel1 cells possess G-quadruplex (G4)-DNA-forming sequences in their promoters and are similarly altered at a transcriptional level in wild-type cells treated with the G4-DNA stabilizer TMPyP4 (5,10,15,20-Tetrakis-(N-methyl-4-pyridyl)porphine). Failure to resolve G4-DNAs formed in the displaced strand of RNA-DNA hybrids in Rtel1 cells is suggested by increased R-loops and elevated transcription-replication collisions (TRCs). Moreover, removal of R-loops by RNaseH1 overexpression suppresses TRCs and alleviates the global replication defects observed in Rtel1 and Rtel1 knockin cells and in wild-type cells treated with TMPyP4. We propose that RTEL1 unwinds G4-DNA/R-loops to avert TRCs, which is important to prevent global deregulation in both transcription and DNA replication.
端粒长度调节因子 1（RTEL1）是一种必需的解旋酶，它可以维持端粒的完整性并促进 DNA 复制。在 Rtel1 缺陷细胞中，复制应激的来源仍不清楚。在这里，我们报告说，RTEL1 的缺失会导致广泛的转录变化，而这些变化与它在端粒上的作用无关。在 Rtel1 细胞中，大多数受影响的基因在其启动子中都具有 G-四链体（G4）-DNA 形成序列，并且在野生型细胞中用 G4-DNA 稳定剂 TMPyP4（5,10,15,20-四（N-甲基-4-吡啶基）卟啉）处理时，它们在转录水平上也会受到类似的改变。在 Rtel1 细胞中，RNA-DNA 杂交体的取代链中形成的 G4-DNA 无法得到解决，这表明 R 环增加，转录-复制碰撞（TRCs）增加。此外，通过过度表达 RNaseH1 去除 R 环可以抑制 TRCs，并缓解在 Rtel1 和 Rtel1 敲入细胞以及用 TMPyP4 处理的野生型细胞中观察到的全局复制缺陷。我们提出，RTEL1 解开 G4-DNA/R 环以避免 TRCs，这对于防止转录和 DNA 复制的全局失调非常重要。
