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Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - RTEL1 Regulates G4/R-Loops to Avert Replication-Transcription Collisions
AU - Kotsantis, Panagiotis
AU - Segura-Bayona, Sandra
AU - Margalef, Pol
AU - Marzec, Paulina
AU - Ruis, Phil
AU - Hewitt, Graeme
AU - Bellelli, Roberto
AU - Patel, Harshil
AU - Goldstone, Robert
AU - Poetsch, Anna R.
AU - Boulton, Simon J.
PY - 2020/12/22
Y1 - 2020/12/22
N2 - 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 PIP_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.
AB - 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 PIP_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.
KW - RTEL1
KW - R-loops
KW - G-quadruplexes
KW - G4-DNA structures
KW - replication stress
KW - transcription
KW - genome instability
U2 - 10.1016/j.celrep.2020.108546
DO - 10.1016/j.celrep.2020.108546
M3 - Journal article
C2 - 33357438
VL - 33
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 12
M1 - 108546
ER -