R-loops: formation, function, and relevance to cell stress
Authors:David F Allison1,2 and Gang Greg Wang1,2
1 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
2 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
Keywords:
R-loops, RNA-DNA hybrid, replication fork stalling, gene transcription, genome instability, mRNA splicing, DNA damage, chromatin modification, cancer, ataxia.
Abbreviations:
AID – activation-induced deaminase,
ds – double-stranded,
DSB – double strand break,
FA – Fanconi Anemia,
G-cluster – guanine-rich cluster,
mRNP – messenger ribonucleoprotein particle,
RF – replication fork,
ss – single-stranded,
TOP – topoisomerase,
TREX – THO and transcription export.
Corresponding Author(s):
Conflict of interest statement:
The authors declare no conflicts of interest.
Please cite this article as:
David F Allison and Gang Greg Wang (2019). R-loops: formation, function, and relevance to cell stress. Cell Stress 3(2): 38-47. doi: 10.15698/cst2019.02.175
© 2019 Allison and Wang. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
Abstract:
Exposure of genomic, single-stranded DNA (ssDNA) during transcription and replication creates opportunities for the formation of inappropriate secondary structures. Cells manage this exposure by using topoisomerases and helicases to reduce the inherent topological stress that arises from unwinding the double helix and by coating ssDNA with protective protein complexes. Interestingly, specific DNA-RNA hybrids, known as R-loops, form during transcription and exist in homeostasis throughout the genomes of prokaryotes and eukaryotes. These hybrids nucleate from guanine rich clusters in the template strand and extend across GC rich spans of transcribed genes. In vivo regulatory functions have evolved from R-loops, including regulation of gene expression and telomere lengthening. However, they also exist as a form of stress, particularly when replication forks collide with the transcription machinery. New methodologies and models are being developed to delineate the biology of R-loops, including those related to cell stress-based diseases like cancer. As accumulation of R-loops is associated with disease, targeting molecular pathways that regulate their formation or removal could provide new avenues for therapeutic intervention. This review covers recent understandings of the molecular basis for R-loop formation, removal, and biological outcomes in the context of cellular stress.