The dark side of RNA:DNA hybrids

RNA:DNA hybrids form when nascent transcripts anneal to the DNA template strand or any homologous DNA region. Co-transcriptional RNA:DNA hybrids, organized in R-loop structures together with the displaced non-transcribed strand, assist gene expression, DNA repair and other physiological cellular functions. A dark side of the matter is that RNA:DNA hybrids are also a cause of DNA damage and human diseases. In this review, we summarize recent advances in the understanding of the mechanisms by which the impairment of hybrid turnover promotes DNA damage and genome instability via the interference with DNA replication and DNA double-strand break repair. We also discuss how hybrids could contribute to cancer, neurodegeneration and susceptibility to viral infections, focusing on dysfunctions associated with the anti-R-loop helicase Senataxin.