Out of balance: R-loops in human disease.

Matthias Groh,Natalia Gromak,Nancy Maizels

doi:10.1371/journal.pgen.1004630

Matthias Groh, Natalia Gromak + Show 1 more

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https://doi.org/10.1371/journal.pgen.1004630

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Journal: PLoS genetics	Publication Date: Sep 18, 2014
Citations: 232	License type: CC BY 4.0

Affiliation: University of Oxford

Abstract

R-loops are cellular structures composed of an RNA/DNA hybrid, which is formed when the RNA hybridises to a complementary DNA strand and a displaced single-stranded DNA. R-loops have been detected in various organisms from bacteria to mammals and play crucial roles in regulating gene expression, DNA and histone modifications, immunoglobulin class switch recombination, DNA replication, and genome stability. Recent evidence suggests that R-loops are also involved in molecular mechanisms of neurological diseases and cancer. In addition, mutations in factors implicated in R-loop biology, such as RNase H and SETX (senataxin), lead to devastating human neurodegenerative disorders, highlighting the importance of correctly regulating the level of R-loops in human cells. In this review we summarise current advances in this field, with a particular focus on diseases associated with dysregulation of R-loop structures. We also discuss potential therapeutic approaches for such diseases and highlight future research directions.

Highlights

R-loops are three-stranded structures, which form when RNA hybridises to a complementary DNA strand, forming an RNA/ DNA hybrid, resulting in displacement of the other DNA strand in this process (Figure 1)
R-loops have been implicated in many biological processes in different organisms
Despite the diversity of these biological processes, the molecular mechanisms associated with R-loop formation in mammalian cells remain largely unknown

Summary

Introduction

R-loops are three-stranded structures, which form when RNA hybridises to a complementary DNA strand, forming an RNA/ DNA hybrid, resulting in displacement of the other DNA strand in this process (Figure 1). Altering the physiological Rloop balance can impair R-loop-regulated processes, cause genome instability, and may lead to human diseases. Recent evidence shows that R-loops can directly affect many gene expression–associated processes, including DNA methylation, posttranslational histone modifications, and transcription, by influencing the function of regulatory proteins [16,18,25,26].

Results

Conclusion