A transcription‐independent mechanism determines rapid periodic fluctuations of BRCA1  expression

Abstract

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. image How expression of BRCA1 is dynamically regulated throughout the cell cycle in cancer cells remains unclear. This study uncovers a critical role for RBM10‐mediated RNA alternative splicing coupled to nonsense‐mediated mRNA decay (AS‐NMD) in determining periodic BRCA1 fluctuations in G1/S‐phase. CDK2‐RBM10‐mediated AS‐NMD determines periodic BRCA1 mRNA expression during the G1/S transition. AS‐NMD‐mediated periodic expression regulation controls gene periodic fluctuations during G1/S transition by altering the proportion of mRNAs degraded while remaining transcriptionally active. Rapid AS‐NMD organizes periodic gene expression throughout the cell cycle. Combination of CDK2 inhibitors with PARP inhibitors is a potential therapeutic strategy.