Increase in harmful R-loops associates with different alterations in mRNP composition

Understanding how the assembly of nascent mRNA into a ribonucleoprotein (mRNP) influences R-loop homeostasis is crucial for gaining insights into the cellular mechanisms that prevent genome instability. Here, we identify three RNA-binding proteins, Rie1, Rim4 and She2, whose stoichiometry is important for limiting R-loop accumulation and, consequently, preventing DNA damage. Notably, Rim4 and She2 are overrepresented in mRNPs assembled in the absence of THO. Additionally, we found that an excess of Dis3 impairs exosome function, promoting R-loops, particularly from non-coding RNAs, that causes genomic instability. Our results indicate that mRNP assembly is a precise process that when perturbed by changes in the availability of different RBPs or RNAs, causes R-loop-mediated DNA damage in the cell. These results may have important implications for understanding the mechanism that promotes cancer, as several RBPs are overexpressed in different types of tumors.