Department of Biology, Technion - Israel Institute of Technology, Haifa, 3200003, Israel.
Nat Commun. 2023 Nov 22;14(1):7628. doi: 10.1038/s41467-023-43495-6.
p53-mediated cell cycle arrest during DNA damage is dependent on the induction of p21 protein, encoded by the CDKN1A gene. p21 inhibits cyclin-dependent kinases required for cell cycle progression to guarantee accurate repair of DNA lesions. Hence, fine-tuning of p21 levels is crucial to preserve genomic stability. Currently, the multilayered regulation of p21 levels during DNA damage is not fully understood. Herein, we identify the human RNA binding motif protein 42 (RBM42) as a regulator of p21 levels during DNA damage. Genome-wide transcriptome and interactome analysis reveals that RBM42 alters the expression of p53-regulated genes during DNA damage. Specifically, we demonstrate that RBM42 facilitates CDKN1A splicing by counteracting the splicing inhibitory effect of RBM4 protein. Unexpectedly, we also show that RBM42, underpins translation of various splicing targets, including CDKN1A. Concordantly, transcriptome-wide mapping of RBM42-RNA interactions using eCLIP further substantiates the dual function of RBM42 in regulating splicing and translation of its target genes, including CDKN1A. Collectively, our data show that RBM42 couples splicing and translation machineries to fine-tune gene expression during DNA damage response.
p53 介导的细胞周期阻滞在 DNA 损伤过程中依赖于 p21 蛋白的诱导，p21 蛋白由 CDKN1A 基因编码。p21 抑制细胞周期进程所需的细胞周期蛋白依赖性激酶，以保证 DNA 损伤的准确修复。因此，精细调节 p21 水平对于维持基因组稳定性至关重要。目前，DNA 损伤过程中 p21 水平的多层调节尚不完全清楚。在此，我们确定人类 RNA 结合基序蛋白 42（RBM42）是 DNA 损伤过程中 p21 水平的调节剂。全基因组转录组和互作组分析表明，RBM42 在 DNA 损伤过程中改变了 p53 调节基因的表达。具体来说，我们证明 RBM42 通过抵消 RBM4 蛋白的剪接抑制作用来促进 CDKN1A 的剪接。出乎意料的是，我们还表明 RBM42 支持各种剪接靶标（包括 CDKN1A）的翻译。相应地，使用 eCLIP 对 RBM42-RNA 相互作用进行全转录组映射进一步证实了 RBM42 在调节其靶基因（包括 CDKN1A）的剪接和翻译中的双重功能。总之，我们的数据表明，RBM42 耦联剪接和翻译机制，以在 DNA 损伤反应中精细调节基因表达。
