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Regulatory R-loops as facilitators of gene expression and genome stability

Abstract

R-loops are three-stranded structures that harbour an RNA–DNA hybrid and frequently form during transcription. R-loop misregulation is associated with DNA damage, transcription elongation defects, hyper-recombination and genome instability. In contrast to such ‘unscheduled’ R-loops, evidence is mounting that cells harness the presence of RNA–DNA hybrids in scheduled, ‘regulatory’ R-loops to promote DNA transactions, including transcription termination and other steps of gene regulation, telomere stability and DNA repair. R-loops formed by cellular RNAs can regulate histone post-translational modification and may be recognized by dedicated reader proteins. The two-faced nature of R-loops implies that their formation, location and timely removal must be tightly regulated. In this Perspective, we discuss the cellular processes that regulatory R-loops modulate, the regulation of R-loops and the potential differences that may exist between regulatory R-loops and unscheduled R-loops.

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Fig. 1: Functional RNA–DNA hybrids.
Fig. 2: R-loops across the genome.
Fig. 3: R-loops as regulators of gene expression.
Fig. 4: R-loops can promote transcription termination.
Fig. 5: RNA–DNA hybrids can promote genome stability.
Fig. 6: Unscheduled versus regulatory R-loops — a model.

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Acknowledgements

The authors apologize to colleagues whose work could not be cited owing to space constraints. They thank R. Otto for help with figures and O. Vydzhak and N. Schindler for feedback on the manuscript. C.N. acknowledges support by a European Research Council (ERC) Advanced Grant (HybReader), and B.L acknowledges support from the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) Heisenberg Program LU 1709/2-1. Both laboratories are funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 393547839 – SFB 1361.

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Niehrs, C., Luke, B. Regulatory R-loops as facilitators of gene expression and genome stability. Nat Rev Mol Cell Biol 21, 167–178 (2020). https://doi.org/10.1038/s41580-019-0206-3

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