ATR-binding lncRNA ScaRNA2 promotes cancer resistance through facilitating efficient DNA end resection during homologous recombination repair.
ATR-binding lncRNA ScaRNA2 promotes cancer resistance through facilitating efficient DNA end resection during homologous recombination repair.
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DOI：
10.1186/s13046-023-02829-4
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发表时间：
2023-09-30
影响因子：
11.3
通讯作者：
Yang, Yanyong
中科院分区：
文献类型：
--
作者：
Chen, Yuanyuan;Shen, Hui;Liu, Tingting;Cao, Kun;Wan, Zhijie;Du, Zhipeng;Wang, Hang;Yu, Yue;Ma, Shengzhe;Lu, Edward;Zhang, Wei;Cai, Jianming;Gao, Fu;Yang, Yanyong
我们先前的研究首次表明ATR结合长非编码RNA（lncRNA）是ATR功能所必需的，并促进癌症抗性。然而，ATR激活中的特异性lncRNA在很大程度上仍然不清楚，这限制了我们对这一关键生物学过程的全面理解。采用RNA免疫沉淀（RIP），然后进行RNA测序，以鉴定ATR结合lncRNA，并使用RIP-qPCR测定进一步验证。免疫荧光染色和Western blotting检测DNA损伤修复因子的活化情况。在确定scaRNA 2对DNA损伤试剂的细胞敏感性的影响后，在患者来源的类器官和异种移植临床前模型中研究了scaRNA 2对放射治疗的影响。scaRNA 2的临床相关性也在从直肠癌患者分离的组织中得到验证。ScaRNA 2被鉴定为最富集的ATR结合lncRNA，并且被发现对于同源重组（HR）介导的DNA损伤修复是必需的。此外，scaRNA 2敲低废除ATR及其底物的募集响应于DNA损伤。从机制上讲，观察到scaRNA 2是Exo 1介导的DNA末端切除所必需的，并将MRN复合物桥接到ATR活化。scaRNA 2的敲低有效地增加了癌细胞对多种DNA损伤相关放化疗的敏感性。在临床前，scaRNA 2的敲低改善了放疗对患者来源的类器官和异种移植模型的影响。最后，与ATR共定位的scaRNA 2的增加也发现在对放射治疗抵抗的临床患者中。ScaRNA 2被鉴定为与ATR结合的最丰富的lncRNA，并被证明可以将DNA末端切除与ATR激活连接起来;因此，它可以用作癌症联合化疗和放疗的有效靶点。在线版本包含补充材料，可通过10.1186/s13046-023-02829-4获得。
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. 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. 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 improved the effects of radiotherapy on patient-derived organoids and xenograft models. Finally, an increase in scaRNA2 colocalized with ATR was also found in clinical patients who were resistant to radiotherapy. ScaRNA2 was identified as the most abundant lncRNA bound to ATR and was demonstrated to bridge DNA end resection to ATR activation; thus, it could be applied as a potent target for combined cancer treatments with chemoradiotherapy. The online version contains supplementary material available at 10.1186/s13046-023-02829-4.
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