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Abstract
Since their discovery, R-loops have been associated with both physiological and pathological functions that are conserved across species. R-loops are a source of replication stress and genome instability, as seen in neurodegenerative disorders and cancer. In response, cells have evolved pathways to prevent R-loop accumulation as well as to resolve them. A growing body of evidence correlates R-loop accumulation with changes in the epigenetic landscape. However, the role of chromatin modification and remodeling in R-loops homeostasis remains unclear. This review covers various mechanisms precluding R-loop accumulation and highlights the role of chromatin modifiers and remodelers in facilitating timely R-loop resolution. We also discuss the enigmatic role of RNA:DNA hybrids in facilitating DNA repair, epigenetic landscape and the potential role of replication fork preservation pathways, active fork stability and stalled fork protection pathways, in avoiding replication-transcription conflicts. Finally, we discuss the potential role of several Chro-Mates (chromatin modifiers and remodelers) in the likely differentiation between persistent/detrimental R-loops and transient/benign R-loops that assist in various physiological processes relevant for therapeutic interventions.
Highlights
The unwinding of the DNA double helix during events such as transcription, DNA replication or DNA repair, offers the opportunity for various anomalies, such as RNA:DNA hybrids or R-loops to form
This study strongly suggests a role for other SWI/SNF remodelers, such as PBRM1 and ARID1A, in regulating chromatin structure at R-loop-derived R-T conflict sites, allowing a more accessible and open chromatin structure that might permit the binding of known factors involved in R-loop resolution such as SETX, RNase H1, BRCA2 and Fanconi Anemia (FA)
Most of the studies to date have focused on the characterization of prevention and removal pathways of RNA:DNA hybrids, while only in recent years has the role of the chromatin landscape been explored
Summary
The unwinding of the DNA double helix during events such as transcription, DNA replication or DNA repair, offers the opportunity for various anomalies, such as RNA:DNA hybrids or R-loops to form. Were named as “R-loops” to depict the three-stranded structure similar to previously described D-loops [2], but with an RNA moiety in the hybrid. It is still not fully understood how R-loops are generated. R-loops were thought to be transient and to be produced only as a byproduct of transcription, but their greater significance is coming to light [7,8,9,10] It is unclear how R-loops are generated, more is known about the regions in which they form and accumulate. In the red box are listed the most noteworthy roles of persistent and detrimental R-loops
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