Genome stability disrupted by the circRBM39(4,5,6)–RPA2 axis represses breast tumorigenesis

Genome instability (GI) is a hallmark of cancer. GI is associated with accumulative DNA damage and tumor-specific defects in DNA repair. Multiple antitumor drugs have been developed to promote persistent GI and to drive DNA damage beyond a threshold that tumor cells can survive. However, regulatory roles of circular RNAs (circRNAs) in GI and DNA damage remain elusive. Through circRNA profiling and a small interfering RNA (siRNA)-mediated screen, we have identified a circRNA termed circRBM39(4,5,6) , which is significantly decreased in breast cancer (BC) and disrupts DNA damage response. CircRBM39(4,5,6) inhibits breast tumorigenesis through increasing DNA damage and promoting sensitivity to the antitumor drug poly Adenosine Diphosphate (ADP-ribose) polymerase inhibitor (PARPi). Mechanistically, cytoplasmic circRBM39(4,5,6) interacts with replication protein A2 (RPA2), an essential DNA repair factor, through a 7-nt AG-rich motif and destabilizes RPA2 protein by facilitating HECT and RCC1-like domain 2 (HERC2)-mediated ubiquitination, thus repressing homologous recombination repair. Importantly, administration of in vitro synthesized circRBM39(4,5,6) substantially inhibits breast tumorigenesis, sensitizes BC cells to PARPi, and renders them susceptible to synthetic lethality (SL) in distinct breast tumorigenesis mouse models. Our findings highlight the interplay between circRNA and GI in cancers, and the SL of circRBM39(4,5,6) to PARPi provides strategies for RNA-based BC therapeutics.