The Arp2/3 inhibitory protein Arpin inhibits homology-directed DNA repair

Background informationArpin, an Arp2/3 inhibitory protein, inhibits lamellipodial protrusions and cell migration. Arpin expression is lost in tumor cells of several cancer types.ResultsHere we analyzed expression levels of Arpin and various markers using Reverse Phase Protein Array (RPPA) in human mammary carcinomas. We found that Arpin protein levels were correlated with those of several DNA damage response markers. Arpin-null cells display enhanced clustering of double stand breaks (DSBs) when cells are treated with a DNA damaging agent, in line with a previously described role of the Arp2/3 complex in promoting DSB clustering for homologous DNA repair (HDR) in the nucleus. Using a specific HDR assay, we further showed that Arpin depletion increased HDR efficiency two-fold through its ability to inactivate the Arp2/3 complex.ConclusionsArpin regulates both cell migration in the cytosol and HDR in the nucleus.SignificanceLoss of Arpin expression coordinates enhanced cell migration with up-regulated DNA repair, which is required when DNA damage is induced by active cell migration. Arpin inhibits the Arp2/3 complex in lamellipodia and thereby regulates cell migration. Here we show that Arpin depletion results enhances double-strand break clustering and increases homology-directed repair (HDR) efficiency in the nucleus, in line with the role of Arp2/3 in HDR. Enhanced migration leads to increased DNA damage and requires up-regulation of DNA repair. Our data suggest that Arpin, through Arp2/3 inhibition, may coordinate HDR with cell migration. image