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RNA–DNA Hybrids: Double-Edged Swords

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RNA–DNA Hybrids: Double-Edged Swords RESEARCH HIGHLIGHTS Nature Reviews Genetics | Published online 21 Nov 2016; doi:10.1038/nrg.2016.153 Henry Steadman/Photodisc/Getty DNA REPAIR RNA–DNA hybrids: double-edged swords RNA–DNA hybrids are associated with DNA from the DSB in both directions and subsequent damage and genome instability and are thus transcript–template hybridization. typically thought of as harmful. A paper in Cell HR-mediated DSB repair involves resection of now reports that RNA–DNA hybrids have a the 5′ strand on either side of the DSB, which functional role in the homologous recombination leaves long single-stranded DNA (ssDNA) (HR)-mediated repair of double strand DNA 3′ overhangs. These ssDNA stretches are bound breaks (DSBs) and serve to protect genome and protected by replication protein A (RPA) integrity in yeast. before completion of the repair process, which Ohle et al. sought to better understand the occurs through invasion of homologous DNA on function of RNase H enzymes, which are known the sister chromatid. The authors reasoned that to degrade RNA–DNA hybrids. To this end, they the ssDNA overhangs could serve as a template generated RNase H deletion mutants of for the transcription generating RNA–DNA Schizosaccharomyces pombe and analysed their hybrids around DSBs. responses to DNA damage. Strains lacking RNase Consistent with this model, induction of DSBs H were highly sensitive to drug-induced DSBs strongly increased RNA polymerase II (Pol II) and contained increased levels of RNA–DNA levels around the cleavage site, indicative of hybrids. To enable further investigation, the active transcription at DSBs. In addition, the authors engineered a system that allowed them recruitment of RPA was strongly impaired in to induce a chromosomal DSB at a specific cells lacking RNase H and increased in cells cleavage site. Following DSB induction, cells overexpressing RNase H. Moreover, overexpression lacking RNase H were seriously impaired in of RNase H greatly extended the length of growth recovery and were unable to carry out RPA-enriched DNA, suggestive of extended 5′ DSB repairs. strand resection as a result of RNA–DNA hybrid The requirement for RNase H in HR-mediated degradation. Together, these findings suggest that DSB repair suggested an inhibitory role for RNA– the presence of ssDNA at DSBs induces DNA hybrids in the repair process. To explore this transcription, generating transient RNA–DNA hypothesis, the researchers targeted RNA–DNA hybrid intermediates that inhibit the speed and hybrids by overexpressing RNase H. This length of 5′ strand resection and RPA recruitment overexpression and presumed destabilization of around DSBs. RNA–DNA hybrids substantially delayed DSB Finally, analysis of small colonies that arose repair and reduced the recovery rate of cells after DNA damage in strains overexpressing RNase following DSB induction, similar to RNase H H revealed a loss of repeat regions around the deletion, suggesting that RNA–DNA hybrids are a cleavage sites. This finding and further functional intermediate in the HR-mediated DSB experiments suggested that RNA–DNA hybrids repair pathway. protect against unwanted recombination between Seeking direct evidence for RNA–DNA hybrid repeat regions on sister chromatids during DSB involvement, the authors searched for hybrids in repair. Thus, contrary to being merely harmful the vicinity of the cleavage site. Following the by-products of transcription, RNA–DNA hybrids induction of DSBs, they detected a strong appear to have important physiological roles in the enrichment of RNA–DNA hybrids around the regulation of DNA repair and the maintenance of DSB; the enrichment was enhanced in cells genome integrity. Denise Waldron lacking RNase H and was abolished by the overexpression of RNase H. Analysis of the ORIGINAL ARTICLE Ohle, C. et al. Transient RNA–DNA hybrids are position of RNA–DNA hybrids suggested that required for efficient double-strand break repair. Cell 167, 1001–1013 (2016) they result from transcription directed outwards NATURE REVIEWS | GENETICS www.nature.com/nrg ©2016 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. .
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