https://orcid.org/0000-0003-2474-551X
![Sample our Medicine, Dentistry, Nursing & Allied Health journals, sign in here to start your FREE access for 14 days]({"type":"image" , "src" : "/sda/5944/TOC-Subject-Sample-2021-Medicine-Dentistry-Nursing-Allied-Health.jpg"})
Abstract
R-loops, intricate three-stranded structures formed by RNA–DNA hybrids and an exposed non-template DNA strand, are fundamental to various biological phenomena. They carry out essential and contrasting functions within cellular mechanisms, underlining their critical role in maintaining cellular homeostasis. The specific cellular context that dictates R-loop formation determines their function, particularly emphasizing the necessity for their meticulous genomic regulation. Notably, the aberrant formation or misregulation of R-loops is implicated in numerous neurological disorders. This review focuses on the complex interactions between R-loops and double-strand DNA breaks, exploring how R-loop dysregulation potentially contributes to the pathogenesis of various brain disorders, which could provide novel insights into the molecular mechanisms underpinning neurological disease progression and identify potential therapeutic targets by highlighting these aspects.
Plain Language Summary
R-loops are special structures inside our cells, made when a piece of RNA (a molecule similar to DNA) sticks to DNA, exposing a part of the DNA. These structures play important roles in how our cells work, helping to keep them healthy and functioning properly. However, when these R-loops do not form correctly or are not controlled well by the cell, they can cause problems. This is especially true in the brain, where mistakes in R-loop formation can lead to various neurological disorders, which are conditions that affect the brain and nerves. In our review, we examine how R-loops interact with certain types of DNA damage and how this can lead to brain disorders. We hope that by understanding these interactions better, scientists can find new ways to treat or prevent these conditions.
Tweetable abstract
Exploring the role of R-loops in neurological disorders: our review highlights how their dysregulation may contribute to disease progression, offering new insights into molecular mechanisms and potential therapeutic avenues.
R-loops are transient three-stranded structures comprised of an RNA–DNA hybrid and a single-stranded non-template DNA strand that play a role in many essential biological processes.
Regulation of R-loops is complex and failure to properly regulate these structures is associated with multiple diseases.
R-loops & DNA damage
R-loops both cause and respond to DNA damage.
Accumulation of R-loops has been linked to increasing DNA damage and cell death by either blocking replication fork progression or through the nature of their structure and excision from the genome.
When formed in response to DSBs, R-loops can serve as signals of DNA damage acting as docking sites for repair proteins such as RPA, RAD52 and RAD51 promoting homologous recombination.
Brain is vulnerable to DNA damage due to high oxygen requirements and post-mitotic state and increased damage levels may be driven by dysregulation of R-loops.
Pathological roles of R-loops in motor neuron diseases
R-loops have emerged as regulators of multiple diseases, including neurological disorders.
Dysregulation of R-loops occurs due to either mutations within genes which regulate these structures or due to trinucleotide repeat expansions.
Most diseases are associated with the accumulation of R-loops, leading to gene dysregulation by blocking RNA Pol II and potentially increasing replication fork collisions or by preventing DMNTs from methylating gene promoters.
R-loops increase fragility of loci as they are highly vulnerable to damage due to their structure.
Future perspective
R-loops potentially play vital roles in neurological disorders.
Increased DNA damage associated with these disorders is linked to dysregulation of R-loops.
R-loops are an interesting potential target for therapeutic action.
Author contributions
K Westover wrote the manuscript and created all figures and tables. B Yao and P Jin edited the manuscript for publication.
Financial disclosure
This review was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number F31NS127537 and the Kirschstein National Research Service Award T32 under award number GM00008940. NIH grants R01MH117122, R01AG062577, R01AG064786, R33NS106120, R01NS118819 and R01AG078937 to B Yao also supported this review. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Competing interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Writing disclosure
No writing assistance was utilized in the production of this manuscript.
Acknowledgments
We would like to acknowledge our funding sources as well as the members of the Yao Lab at Emory University. All figures created with BioRender.com.