A novel role for UPF1 in safeguarding DNA replication in S phase and beyond

Maintaining DNA replication fidelity is paramount in allowing for the successful duplication of genetic information, that will be passed on to the next generation of daughter cells. Interfering with this process leads to replication stress that can promote mutagenesis, double-stranded DNA breaks and loss of genetic stability. The fundamental process of transcription is a well described promotor of DNA replication stress through changes in chromatin dynamics, DNA structure and direct transcription-replication collisions (TRCS). Here we have identified a novel function for the RNA/DNA helicase UPF1 in preventing harmful consequences between the DNA replicative and transcriptional machineries. Loss of UPF1 resulted in an increase in spontaneous transcription-dependent replication fork stalling and double stranded breaks. UPF1-deficient cells following mild replicative stress show a reduced frequency of replication fork stalling, mitotic delay and the DNA replication salvage pathway of mitotic DNA synthesis (MiDAS). Together these data demonstrate UPF1 as vital for protecting the genome from spontaneous TRCs, most likely through its role in regulating the dissociation of nascent R-loop associated-mRNAs. Loss or down-regulation of UPF1 also represents a potential mechanism whereby cells could display resistance to DNA replication-targeting chemotherapeutics. Targeting UPF1-deficient cancers or UPF1 inhibition with drugs known to synergize with high levels of TRCs such as PARP inhibitors, could be a promising therapeutic approach.