R-Loops and Its Chro-Mates: The Strange Case of Dr. Jekyll and Mr. Hyde

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.

The CHCHD2/Sirt1 corepressors involve in G9a-mediated regulation of RNase H1 expression to control R-loop

“…R-loops are involved in several cellular processes in physiological contexts, such as gene expression, transcription termination, DNA repair, telomere maintenance, Okazaki fragment maturation, and immunoglobulin class-switch recombination ( Crossley et al., 2019 ; Skourti-Stathaki & Proudfoot, 2014 ). However, R-loops are also considered a double-edged sword, which is a source of replication stress and genome instability causing DNA damage, such as DSBs accumulation ( Uruci et al., 2021 ). RNase H, topoisomerases, and RNA helicases are part of the R-loop degradation machinery associated with the decrease of RNA/DNA hybrids in mammalian cells ( Cristini et al., 2018 ; Parajuli et al., 2017 ; Song et al., 2017 ; Yang et al., 2014 ).…”

DDM1-mediated R-loop resolution and H2A.Z exclusion facilitates heterochromatin formation in Arabidopsis

“…S6) (9,13,39). Given that chromatin remodelers have been reported to be associated with R-loop abundance in vivo (40)(41)(42)(43) [reviewed in (44)], we decided to investigate the possibility of DDM1 in removing RNA:DNA hybrids and R-loops. First, we performed ATP hydrolysis assays to examine adenosine triphosphatase (ATPase) activity of DDM1 using different forms of nucleic acid as substrate.…”

R‐loop: The new genome regulatory element in plants

“…Chromatin condensation is primarily altered by various histone modifications and histone variant deposition, which are achieved by chromatin remodelers (Clapier et al, 2017). Recent evidence has demonstrated connections between chromatin remodelers and R-loops (Uruci et al, 2021). The inositol requiring 80 (INO80) family is one of four subfamilies of Sucrose non-fermenting 2 (Snf2)-like remodelers that consists of the INO80 and Swi2/Snf2-related (SWR1) complexes (Poli et al, 2017).…”

“…Chromatin condensation determines the state of transcription and replication and is also linked to R‐loop formation across the genome (Uruci et al, 2021). Chromatin condensation is primarily altered by various histone modifications and histone variant deposition, which are achieved by chromatin remodelers (Clapier et al, 2017).…”