Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.21.214700v1?rss=1 Authors: Sarni, D., Shtrikman, A., Oren, Y. S., Kerem, B. Abstract: DNA replication is a complex process that is tightly regulated to ensure faithful genome duplication, and its perturbation leads to DNA damage and genomic instability. Oncogene expression triggers replicative stress that can lead to genetic instability, driving cancer progression. Thus, revealing the molecular basis for oncogene-induced replication stress is important for understanding of oncogenesis. Here we show that the activation of mutated HRAS leads to a non-canonical replication stress characterized by accelerated replication rate, inducing DNA damage. Mutated HRAS increases topoisomerase 1 (TOP1) expression, which leads to reduced levels of RNA-DNA hybrids (R-loops), driving fork acceleration and damage formation. Restoration of the perturbed replication either by restoration of TOP1 levels or directly by mild replication inhibition results in a dramatic reduction in DNA damage. The findings highlight the importance of TOP1 equilibrium in the regulation of R-loop homeostasis to ensure faithful DNA replication and genome integrity that when dysregulated can be a mechanism of oncogene-induced DNA damage. Copy rights belong to original authors. Visit the link for more info