LncRNA scaRNA2 bridges DNA end-resection to homologous recombination repair mediated chemoradioresistance

Abstract As a potent target for cancer therapy, ATR mainly regulates homologous recombination (HR)-mediated DNA damage repair. Our previous study first identified that ATR binding long noncoding RNA (lncRNA) is necessary for ATR function and promotes cancer resistance. However, most important lncRNAs, as critical factors for ATR activation, are largely unknown. In the present study, scaRNA2, the most enriched ATR-binding lncRNA, was identified and well characterized. ScaRNA2 was found to be essential for HR-mediated DNA damage repair. Furthermore, scaRNA2 knockdown abrogated the mobilization of ATR and its substrates in response to DNA damage. Mechanistically, scaRNA2 was observed to be necessary for Exo1-mediated DNA end resection and bridged the MRN complex to ATR activation. Using cancer cells and a cell-derived xenograft model, we demonstrated that lentivirus-based knockdown of scaRNA2 effectively increases sensitivity to multiple kinds of chemoradiotherapy. Preclinically, knockdown of scaRNA2 improved the therapeutic effects of radiotherapy on patient-derived organoids and xenograft models. Finally, upregulation of scaRNA2 colocalized with ATR was also found in clinical patients who are resistant to radiotherapy based on tumor regression grades. In conclusion, we identified scaRNA2 as the most abundant lncRNA bound to ATR and uncovered its mechanism in bridging DNA end resection to ATR activation, which could be applied as a potent target for combined cancer treatments with chemoradiotherapy.