Genomic DNA can be prone to endogenous nicks. The contribution of DNA nicks to genome instability includes the breakage of double-stranded DNA due to single-stranded DNA nicking. A recent study mapped the genome-wide distribution of endogenous DNA nicks suggesting that transcription contributes to the formation and distribution of DNA nicks. R-loops are a byproduct of transcription, and nicked DNA seems to contribute to R-loop formation and vice versa. Here, I want discuss the possibility that the 3'OH of nicked DNA at R-loops could trigger unscheduled replication events.