p53 activates circASCC3 to repress R- loops and enhance resistance to chemotherapy

• 成果类型: Article
• 署名作者: 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
• 署名单位: Fudan University; Fudan University; Fudan University; Fudan University; Nanchang University; Capital Medical University; Fudan University; Fudan University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11754
• DOI: 10.1073/pnas.2415869122
• 发表日期: 2025-03-18
• 关键词: pause sites; dna-repair; cancer; survival; rna

摘要

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 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 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 and potentially contributes to chemoresistance.