Atypical R-loops in cancer: decoding molecular chaos for therapeutic gain

R-loop is a special DNA-RNA hybrid genomic structure. Since its identification, the molecular mechanisms of physiological processes such as class switch recombination have been revealed, uncontrolled regulation of which has become the underlying cause of many diseases. With the development of molecular biology techniques, R-loops found at different sites and formed via different mechanisms have been discovered. These non-classical R-loops participate in various cellular activities via different mechanisms. A set of sophisticated regulatory mechanisms are required to control the number of various R-loops in vivo. The levels of non-classical R-loops in tumor cells differ significantly from those in normal cells; in addition, the regulatory mechanisms for establishing R-loop homeostasis differ, which may be utilized to develop breakthrough therapies for various tumors. In this review, we summarize the current state of knowledge regarding non-classical R-loops in tumor cells, the mechanisms that promote or inhibit this structure, the effects of this structure on tumor cells, and the possible therapeutic targets. By systematically elucidating the pathogenic mechanisms of atypical R-loops, we can achieve precision targeting of tumors and revolutionize clinical precision oncology.