R-Loops and R-Loop-Binding Proteins in Cancer Progression and Drug Resistance

Abstract

R-loops are three-stranded DNA/RNA hybrids that form by the annealing of the mRNA transcript to its coding template while displacing the non-coding strand. While R-loop formation regulates physiological genomic and mitochondrial transcription and DNA damage response, imbalanced R-loop formation can be a threat to the genomic integrity of the cell. As such, R-loop formation is a double-edged sword in cancer progression, and perturbed R-loop homeostasis is observed across various malignancies. Here, we discuss the interplay between R-loops and tumor suppressors and oncogenes, with a focus on BRCA1/2 and ATR. R-loop imbalances contribute to cancer propagation and the development of chemotherapy drug resistance. We explore how R-loop formation can cause cancer cell death in response to chemotherapeutics and be used to circumvent drug resistance. As R-loop formation is tightly linked to mRNA transcription, their formation is unavoidable in cancer cells and can thus be explored in novel cancer therapeutics.

Multifaceted nucleic acid probing with a rationally upgraded molecular rotor

“…Particularly prevalent at promoters, R-loops modulate gene expression through different mechanisms. 57 Consequently, targeting R-loops emerges as a potentially promising strategy for disease treatment. However, there is no method capable of profiling the interaction between DNA/RNA and a large number of small molecules.…”

Analyzing the Effects of Single Nucleotide Polymorphisms on hnRNPA2/B1 Protein Stability and Function: Insights for Anticancer Therapeutic Design

“…The stability of the genome and RNA:DNA hybrids are regulated by m6A depositions. Also, the formation of R-loops is common in DNA:RNA hydrides, and these are associated with genomic chaos in malignant cells . Furthermore, recent work by Humphries and Fitzgerald showed that hnRNPA2/B1 acts as a nuclear receptor for herpes virus (dsDNA) and via a cGAS-independent pathway, it activates a type-I interferon (IFN) response .…”

“…Also, the formation of R-loops is common in DNA:RNA hydrides, and these are associated with genomic chaos in malignant cells. 28 Furthermore, recent work by Humphries and Fitzgerald 29 showed that hnRNPA2/B1 acts as a nuclear receptor for herpes virus (dsDNA) and via a cGAS-independent pathway, it activates a type-I interferon (IFN) response. 30 And hnRNPA2/B1 can amplify the antiviral response by controlling the exportations of cGAS and STING mRNAs.…”