ATR-binding lncRNA ScaRNA2 promotes cancer resistance through facilitating efficient DNA end resection during homologous recombination repair

作者：Yuanyuan Chen, Hui Shen, Tingting Liu, Kun Cao, Zhijie Wan, Zhipeng Du, Hang Wang, Yue Yu, Shengzhe Ma, Edward S. Lu, Wei Zhang, Jianming Cai, Fu Gao, Yanyong Yang · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2023 · DOI：10.1186/s13046-023-02829-4 · 被引用次数：12 · 研究领域：Cancer-related molecular mechanisms research、DNA Repair Mechanisms、RNA Research and Splicing

BACKGROUND: Our previous study first showed that ATR-binding long noncoding RNA (lncRNA) is necessary for ATR function and promotes cancer resistance. However, the specific lncRNAs instrumental in ATR activation remain largely unclear, which limits our comprehensive understanding of this critical biological process. METHODS: RNA immunoprecipitation (RIP) followed by RNA sequencing was employed to identify ATR-binding lncRNAs, which were further validated using RIP-qPCR assays. Immunofluorescence staining and Western blotting were applied to detect the activation of DNA damage repair factors. After the effect of scaRNA2 on cellular sensitivity to DNA-damaging reagents was determined, the effects of scaRNA2 on radiotherapy were investigated in patient-derived organoids and xenograft preclinical models. The clinical relevance of scaRNA2 was also validated in tissues isolated from rectal cancer patients. RESULTS: ScaRNA2 was identified as the most enriched ATR-binding lncRNA and was found to be essential for homologous recombination (HR) mediated DNA damage repair. Furthermore, scaRNA2 knockdown abrogated the recruitment 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. Knockdown of scaRNA2 effectively increased the sensitivity of cancer cells to multiple kinds of DNA damage-related chemoradiotherapy. Preclinically, knockdown of scaRNA2 impro...