R-Loops at Chromosome Ends: From Formation, Regulation, and Cellular Consequence

SIMPLE SUMMARY: R-loops, also referred to as RNA: DNA hybrids, are tripartite structures formed when a single-stranded RNA molecule forms a complex with a double-stranded DNA duplex via homology-directed base pairing. Many cellular functions are thought to be mediated by R-loops, including gene regulation, DNA replication, chromatin patterning, and DNA repair. R-loops are common and dynamic structures that account for up to 5% of mammalian genomes. In this review, we present an updated review of R-loops at a specific locus, telomeres. We summarize recent advances in the protein factors that regulate the formation and resolution of R-loops at telomeres. We also discuss the role of persistent or unscheduled R-loops in promoting genome and telomere instability and their links to human diseases. ABSTRACT: Telomeric repeat containing RNA (TERRA) is transcribed from subtelomeric regions to telomeres. TERRA RNA can invade telomeric dsDNA and form telomeric R-loop structures. A growing body of evidence suggests that TERRA-mediated R-loops are critical players in telomere length homeostasis. Here, we will review current knowledge on the regulation of R-loop levels at telomeres. In particular, we will discuss how the central player TERRA and its binding proteins modulate R-loop levels through various mechanisms. We will further provide an overview of the consequences of TERRA-mediated persistent or unscheduled R-loops at telomeres in human ALT cancers and other organisms, with a focus on telomere length regulation after replication interference-induced damage and DNA homologous recombination-mediated repair.