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Genome instability

Breaking the loop: RNA–DNA hybrids escape to the cytoplasm

Nature Structural & Molecular Biology volume 30, page 134 (2023)Cite this article

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Utilizing a microscopy-based system that tracks endogenous R-loops, the authors first confirm that depletion of factors involved in nuclear processing of R-loops, such as BRCA1 or senataxin (SETX), leads to increased cytoRDHs. They observe such hybrids by developing a purification method named cytoplasmic DNA–RNA hybrid immunoprecipitation (cytoDRIP). Notably, the formation of cytoRDHs depends on both the endonuclease XPG, which is known to process nuclear R-loops, and exportin-1, which actively exports nucleic acids to the cytoplasm. Conversely, the authors provide evidence that cytoRDHs are neither apoptotic by-products nor DNA replication dependent.

By combining cytoDRIP with strand-specific RNA–DNA hybrid sequencing, the authors then map the genomic origins of cytoRDHs after loss of SETX and observe an overlap with nuclear R-loops, although only a limited subset of nuclear R-loops seems to be processed to generate cytoRDHs. From a mechanistic perspective, cytoRDHs seem to originate from repeat DNA sequences, long-lived RNase H-resistant nuclear R-loops, and genomic regions containing neighboring nuclear RNA–DNA hybrids in a head-on orientation. However, none of these factors are sufficient determinants on their own. Importantly, rare cytoRDHs that occur under unperturbed conditions share characteristics very similar to those of cytoRDHs that arise after SETX depletion, which suggests that the XPG nuclease may also counteract persistent R-loops under basal conditions.

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Reference

  1. Crossley, M. P. et al. R-loop-derived cytoplasmic RNA–DNA hybrids activate an immune response. Nature https://doi.org/10.1038/s41586-022-05545-9 (2022).

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  1. Nature Structural & Molecular Biology https://www.nature.com/nsmb/

    Dimitris Typas

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  1. Dimitris Typas
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Correspondence to Dimitris Typas.

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Typas, D. Breaking the loop: RNA–DNA hybrids escape to the cytoplasm. Nat Struct Mol Biol 30, 134 (2023). https://doi.org/10.1038/s41594-023-00931-x

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  • DOI: https://doi.org/10.1038/s41594-023-00931-x

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