环状 RNA (circRNA) 是共价闭合 RNA 分子，在真核生物中广泛表达，并在包括癌症在内的多种病理学中失调。许多研究指出它们作为 microRNA (miRNA) 和蛋白质海绵的活性；然而，我们提出了一种基于 circRNA-mRNA 相互作用的功能来调节 mRNA 的命运。我们发现，与肿瘤广泛相关的 circHIPK3 在体内通过人类癌细胞的反向剪接区域直接与 BRCA1 mRNA 相互作用。这种相互作用通过竞争脆性 X 智力迟钝 1 蛋白 (FMRP) 的结合来增加 BRCA1 翻译，我们将其确定为 BRCA1 翻译抑制蛋白。 CircHIPK3 的耗竭或 circRNA-mRNA 相互作用的破坏会降低 BRCA1 蛋白水平并增加 DNA 损伤，使几种癌细胞对 DNA 损伤诱导剂敏感，并使它们容易受到合成致死的影响。此外，用锁核酸 (LNA) 阻断 FMRP 与 BRCA1 mRNA 的相互作用可恢复 BRCA1 半合子乳腺癌细胞中的生理蛋白水平，强调了这种 circRNA-mRNA 相互作用在调节 DNA 损伤反应中的重要性。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Circular RNAs (circRNAs) are covalently closed RNA molecules widely expressed in eukaryotes and deregulated in several pathologies, including cancer. Many studies point to their activity as microRNAs (miRNAs) and protein sponges; however, we propose a function based on circRNA-mRNA interaction to regulate mRNA fate. We show that the widely tumor-associated circHIPK3 directly interacts in vivo with the BRCA1 mRNA through the back-splicing region in human cancer cells. This interaction increases BRCA1 translation by competing for the binding of the fragile-X mental retardation 1 protein (FMRP) protein, which we identified as a BRCA1 translational repressor. CircHIPK3 depletion or disruption of the circRNA-mRNA interaction decreases BRCA1 protein levels and increases DNA damage, sensitizing several cancer cells to DNA-damage-inducing agents and rendering them susceptible to synthetic lethality. Additionally, blocking FMRP interaction with BRCA1 mRNA with locked nucleic acid (LNA) restores physiological protein levels in BRCA1 hemizygous breast cancer cells, underscoring the importance of this circRNA-mRNA interaction in regulating DNA-damage response.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.