Department of Radiation Medicine, School of Basic Medical Sciences, Peking University International Cancer Institute, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, China.
Department of Medical Bioinformatics, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
EMBO J. 2023 Aug 1;42(15):e111951. doi: 10.15252/embj.2022111951. Epub 2023 Jun 19.
BRCA1 expression is highly regulated to prevent genomic instability and tumorigenesis. Dysregulation of BRCA1 expression correlates closely with sporadic basal-like breast cancer and ovarian cancer. The most significant characteristic of BRCA1 regulation is periodic expression fluctuation throughout the cell cycle, which is important for the orderly progression of different DNA repair pathways throughout the various cell cycle phases and for further genomic stability. However, the underlying mechanism driving this phenomenon is poorly understood. Here, we demonstrate that RBM10-mediated RNA alternative splicing coupled to nonsense-mediated mRNA decay (AS-NMD), rather than transcription, determines the periodic fluctuations in G1/S-phase BRCA1 expression. Furthermore, AS-NMD broadly regulates the expression of period genes, such as DNA replication-related genes, in an uneconomical but more rapid manner. In summary, we identified an unexpected posttranscriptional mechanism distinct from canonical processes that mediates the rapid regulation of BRCA1 as well as other period gene expression during the G1/S-phase transition and provided insights into potential targets for cancer therapy.
BRCA1 的表达受到高度调控，以防止基因组不稳定和肿瘤发生。BRCA1 表达失调与散发性基底样乳腺癌和卵巢癌密切相关。BRCA1 调控的最显著特征是整个细胞周期中周期性的表达波动，这对于不同 DNA 修复途径在各个细胞周期阶段的有序进行以及进一步的基因组稳定性非常重要。然而，驱动这种现象的潜在机制还了解甚少。在这里，我们证明 RBM10 介导的 RNA 可变剪接与无义介导的 mRNA 降解（AS-NMD）耦联，而不是转录，决定了 G1/S 期 BRCA1 表达的周期性波动。此外，AS-NMD 以一种不经济但更快速的方式广泛调节周期基因的表达，如与 DNA 复制相关的基因。总之，我们确定了一种与经典过程不同的意外的转录后机制，该机制介导了 BRCA1 以及其他周期基因在 G1/S 期转换过程中的快速表达调控，并为癌症治疗提供了潜在的靶点。
