Cao Mingming, Gan Yu, Huang Yingdan, Tong Jing, Xiong Chen, Chen Yajie, Chen Bing, Huang Ruixuan, Xie Bangxiang, Deng Jun, Huang Shenglin, He Xianghuo, Hao Qian, Zhou Xiang
Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Proc Natl Acad Sci U S A. 2025 Mar 18;122(11):e2415869122. doi: 10.1073/pnas.2415869122. Epub 2025 Mar 11.
The tumor suppressor p53 can trigger tumor resistance to chemotherapy by facilitating DNA damage repair and maintaining genomic integrity. Here, we report that a p53-induced circular RNA circASCC3 promotes chemotherapeutic resistance by resolving R-loops. Our results reveal that p53 directly activates the transcription of , the host gene of circASCC3. In addition, the RNA-binding protein SFPQ is identified to inhibit the formation of circASCC3 by associating with its flanking regions. Importantly, p53 facilitates the formation of circASCC3 by repressing the expression of SFPQ. CircASCC3 has a marginal effect on the survival and growth of cancer cells under normal growing conditions but surprisingly boosts their survival and growth in response to DNA damage stress. Mechanistic analysis reveals that circASCC3 binds to the DEAD-box RNA helicase DDX5 to inhibit its proteasomal degradation. This results in the prevention of R-loop accumulation due to DNA damage, thereby conferring tumor resistance to chemotherapy. Together, our study uncovers that p53 activates circASCC3 to promote R-loop resolution, which maintains genomic stability and potentially contributes to chemoresistance.
肿瘤抑制因子p53可通过促进DNA损伤修复和维持基因组完整性来引发肿瘤对化疗的抗性。在此，我们报告p53诱导的环状RNA circASCC3通过解决R环来促进化疗抗性。我们的结果表明，p53直接激活circASCC3宿主基因的转录。此外，鉴定出RNA结合蛋白SFPQ通过与其侧翼区域结合来抑制circASCC3的形成。重要的是，p53通过抑制SFPQ的表达来促进circASCC3的形成。CircASCC3在正常生长条件下对癌细胞的存活和生长影响不大，但令人惊讶的是，在DNA损伤应激反应中可促进其存活和生长。机制分析表明，circASCC3与DEAD-box RNA解旋酶DDX5结合以抑制其蛋白酶体降解。这导致防止因DNA损伤引起的R环积累，从而赋予肿瘤对化疗的抗性。总之，我们的研究发现p53激活circASCC3以促进R环的解决，这维持了基因组稳定性并可能导致化疗抗性。
