Activation of oncogenes in healthy cells leads to a permanent cell cycle arrest termed oncogene-induced senescence (OIS) characterized by increased DNA damage and deep epigenetic resetting. Bypassing this premalignant state promotes tumorigenesis. Here, we show that cells entering OIS accumulate high levels of three-stranded RNA–DNA hybrids named R-loops, posing a threat to DNA replication and repair. OIS escape is characterized by the resolution of this extra load of R-loops specifically in genomic regions marked by irreparable damage in OIS. In these loci, the heterotrimeric RPA complex performs quality control over R-loop processing by RNaseH1, reducing the amount of DNA damage and allowing re-entry into the cell cycle. In OIS, hyperphosphorylation of RPA32 decreases the affinity of RPA for RNaseH1; in turn, RNaseH1 loses processivity toward R-loops, leading to double-strand breaks (DSBs) accumulation. These results point to a molecular mechanism that controls R-loop processing and acts as a genome caretaker.