Journal
EMBO JOURNAL
Volume 38, Issue 3, Pages -Publisher
WILEY
DOI: 10.15252/embj.201899793
Keywords
DNA secondary structures; PrimPol; replication; repriming; R-loops
Categories
Funding
- Wellcome Trust strategic award [101126/B/13/Z]
- LMB Cambridge International Scholarship
- UKRI Innovation Fellowship
- MRC [U105178808]
- BBSRC [BB/H019723/1, BB/M008800/1]
- University of Sussex PhD studentship
- Wellcome Trust Investigator Award [107928/Z/15/Z]
- ERC Advanced Grant [339170]
- Wellcome Trust [101126/B/13/Z, 107928/Z/15/Z] Funding Source: Wellcome Trust
- BBSRC [BB/S008691/1, BB/H019723/1, BB/M008800/1] Funding Source: UKRI
- MRC [MC_EX_MR/S300001/1, MC_U105178808] Funding Source: UKRI
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During DNA replication, conflicts with ongoing transcription are frequent and require careful management to avoid genetic instability. R-loops, three-stranded nucleic acid structures comprising a DNA:RNA hybrid and displaced single-stranded DNA, are important drivers of damage arising from such conflicts. How R-loops stall replication and the mechanisms that restrain their formation during S phase are incompletely understood. Here, we show in vivo how R-loop formation drives a short purine-rich repeat, (GAA)(10), to become a replication impediment that engages the repriming activity of the primase-polymerase PrimPol. Further, the absence of PrimPol leads to significantly increased R-loop formation around this repeat during S phase. We extend this observation by showing that PrimPol suppresses R-loop formation in genes harbouring secondary structure-forming sequences, exemplified by G quadruplex and H-DNA motifs, across the genome in both avian and human cells. Thus, R-loops promote the creation of replication blocks at susceptible structure-forming sequences, while PrimPol-dependent repriming limits the extent of unscheduled R-loop formation at these sequences, mitigating their impact on replication.
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