PhD Graduate Seminar- Bella Ben-Oz
04/04/2023 13:00
Bella Ben-Oz

A dual role of RBM42 in modulating splicing and translation during DNA damage response: A spotlight on CDKN1A/p21 gene



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 for maintaining genomic stability. Currently, the multilayered regulation of p21 levels during DNA damage is not fully understood. Herein, we identified the human RNA binding motif protein 42 (RBM42) as a novel regulator of p21 levels during DNA damage. Genome-wide transcriptome and interactome analysis revealed that RBM42 alters the expression of p53-regulated genes during DNA damage. Specifically, we demonstrated that RBM42 facilitates CDKN1A splicing during DNA damage by counteracting the splicing inhibitory activity of RBM4 protein. Unexpectedly, we also showed that RBM42 together with its proximity translation factor, CUGBP1, underpins translation of various splicing targets, including CDKN1A, following DNA damage. Concordantly, transcriptome-wide mapping of RBM42-RNA interactions using eCLIP revealed that following DNA damage, RBM42 binds the 5’UTR of hundreds of genes. These findings suggest that RBM42 is primarily involved in modulating DNA damage-induced translation. Collectively, our data show that RBM42 couples splicing and translation machineries to fine-tune gene expression during DNA damage response.