R-Loops in Genome Instability and Cancer

Simple Summary R-loops are three-stranded structures consisting of an RNA-DNA hybrid and an unpaired single-stranded DNA (ssDNA), with biological implications in cellular physiology and pathological conditions. R-loops interfere with DNA repair pathways and activate oncogenes, leading to dysregulated cell proliferation, genome instability, and cancer development. R-loops accumulate in several types of cancer cells, including breast, ovarian, prostate, and lung cancer. Studying the biological roles of R-loops in cancer development is potentially beneficial for innovative diagnostic and treatment approaches for cancer. In this review, we focus on recent advances in R-loops' roles in genome instability, DNA repair, and oncogenic events.Abstract R-loops are unique, three-stranded nucleic acid structures that primarily form when an RNA molecule displaces one DNA strand and anneals to the complementary DNA strand in a double-stranded DNA molecule. R-loop formation can occur during natural processes, such as transcription, in which the nascent RNA molecule remains hybridized with the template DNA strand, while the non-template DNA strand is displaced. However, R-loops can also arise due to many non-natural processes, including DNA damage, dysregulation of RNA degradation pathways, and defects in RNA processing. Despite their prevalence throughout the whole genome, R-loops are predominantly found in actively transcribed gene regions, enabling R-loops to serve seemingly controversial roles. On one hand, the pathological accumulation of R-loops contributes to genome instability, a hallmark of cancer development that plays a role in tumorigenesis, cancer progression, and therapeutic resistance. On the other hand, R-loops play critical roles in regulating essential processes, such as gene expression, chromatin organization, class-switch recombination, mitochondrial DNA replication, and DNA repair. In this review, we summarize discoveries related to the formation, suppression, and removal of R-loops and their influence on genome instability, DNA repair, and oncogenic events. We have also discussed therapeutical opportunities by targeting pathological R-loops.