Abstract
For nearly three decades, R loops have been closely linked with class switch recombination (CSR), the process that generates antibody isotypes and that occurs via a complex cascade initiated by transcription-coupled mutagenesis in switch recombination sequences. R loops form during transcription of switch recombination sequences in vitro and in vivo, and there is solid evidence that R loops are required for efficient class switching. The classical model of R loops posits that they boost mutation rates by generating stable and long tracts of single-stranded DNA that serve as the substrate for activation induced deaminase (AID), the enzyme that initiates the CSR reaction cascade by co-transcriptionally mutating ssDNA in switch recombination sequences. Though logical and compelling, this model has not been supported by in vivo evidence. Indeed, several reports suggest that R loops may not be involved in recruiting AID activity to switch regions, meaning that R loops probably serve other unanticipated roles in CSR. Here, I review the key findings in this field to date and propose hypotheses that could help towards elucidating the precise function of R loops in CSR.
Highlights
R loops are structures that form when nascent RNA stably hybridizes to its template DNA resulting in the non-template DNA strand being extruded as long, stable single-stranded DNA
Initial evidence that transcribed immunoglobulin heavy chain (IgH) switch regions generate R loops came from in vitro transcription experiments where RNA/DNA hybrids were detected during transcription of IgH switch α (Sα) sequences by bacterial polymerases, suggesting that the transcribed RNA was stably bound to the template DNA [31]
After nearly three decades of research, we have learned that R loops are stable intermediates of class switch recombination (CSR) and, more importantly, that R loop frequency correlates with the efficiency of CSR
Summary
R loops are structures that form when nascent RNA stably hybridizes to its template DNA resulting in the non-template DNA strand being extruded as long, stable single-stranded DNA (ssDNA). An excess of R loops has been associated with increased formation of DNA breaks, replication fork stalling, and collisions between transcription and replication complexes, all of which can lead to genome instability [6,7]. B cell activation upon antigen encounter leads to expression of the activation induced induced deaminase (AID), which generates mutations in ssDNA in co-transcriptional manner mostly deaminase (AID), which generates mutations in ssDNA in co-transcriptional manner mostly in the in the VDJ and switch regions (indicated by the mutation spectra). The repetitive switch regions range from 2 kb to 12 kb, and switch sequences and switch sequences have high G clustering and high overall G-richness on the non-template strand have high G clustering and high overall G-richness on the non-template strand (a representative stretch (a representative stretch of switch region sequence is depicted) Upon transcription, these G-rich of switch sequence is depicted).
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