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RTEL1 regulates G4/R-loops to avert replication-transcription collisions.

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journal contribution
posted on 15.01.2021, 09:40 by Panagiotis Kotsantis, Sandra Segura-Bayona, Pol Margalef, Paulina Marzec, Phil Ruis, Graeme Hewitt, Roberto Bellelli, Harshil Patel, Robert Goldstone, Anna R Poetsch, Simon J Boulton
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 Rtel1PIP_box 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.

Funding

Crick (Grant ID: 10048, Grant title: Boulton FC001048) European Research Council (Grant ID: 742437 - TelMetab, Grant title: ERC 742437 - TelMetab)

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