Emerging roles of DNA topoisomerases in the regulation of R-loops

Abstract

R-loops are comprised of a DNA:RNA hybrid and a displaced single-strand DNA (ssDNA) that reinvades the DNA duplex behind the moving RNA polymerase. Because they have several physiological functions within the cell, including gene expression, chromosomal segregation, and mitochondrial DNA replication, among others, R-loop homeostasis is tightly regulated to ensure normal functioning of cellular processes. Thus, several classes of enzymes including RNases, helicases, topoisomerases, as well as proteins involved in splicing and the biogenesis of messenger ribonucleoproteins, have been implicated in R-loop prevention, suppression, and resolution. There exist six topoisomerase enzymes encoded by the human genome that function to introduce transient DNA breaks to relax supercoiled DNA. In this mini-review, we discuss functions of DNA topoisomerases and their emerging role in transcription, replication, and regulation of R-loops, and we highlight how their role in maintaining genome stability can be exploited for cancer therapy.