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

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  • Bella M. Ben-Oz

    (Technion - Israel Institute of Technology)

  • Feras E. Machour

    (Technion - Israel Institute of Technology)

  • Marian Nicola

    (Technion - Israel Institute of Technology)

  • Amir Argoetti

    (Technion - Israel Institute of Technology)

  • Galia Polyak

    (Technion - Israel Institute of Technology)

  • Rawad Hanna

    (Technion - Israel Institute of Technology)

  • Oded Kleifeld

    (Technion - Israel Institute of Technology)

  • Yael Mandel-Gutfreund

    (Technion - Israel Institute of Technology)

  • Nabieh Ayoub

    (Technion - Israel Institute of Technology)

Abstract

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.

Suggested Citation

  • Bella M. Ben-Oz & Feras E. Machour & Marian Nicola & Amir Argoetti & Galia Polyak & Rawad Hanna & Oded Kleifeld & Yael Mandel-Gutfreund & Nabieh Ayoub, 2023. "A dual role of RBM42 in modulating splicing and translation of CDKN1A/p21 during DNA damage response," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43495-6
    DOI: 10.1038/s41467-023-43495-6
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    References listed on IDEAS

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    1. Carsten Boesler & Norbert Rigo & Maria M. Anokhina & Marcel J. Tauchert & Dmitry E. Agafonov & Berthold Kastner & Henning Urlaub & Ralf Ficner & Cindy L. Will & Reinhard Lührmann, 2016. "A spliceosome intermediate with loosely associated tri-snRNP accumulates in the absence of Prp28 ATPase activity," Nature Communications, Nature, vol. 7(1), pages 1-12, November.
    2. Marina Farkas & Hideharu Hashimoto & Yingtao Bi & Ramana V. Davuluri & Lois Resnick-Silverman & James J. Manfredi & Erik W. Debler & Steven B. McMahon, 2021. "Distinct mechanisms control genome recognition by p53 at its target genes linked to different cell fates," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. James Uniacke & Chet E. Holterman & Gabriel Lachance & Aleksandra Franovic & Mathieu D. Jacob & Marc R. Fabian & Josianne Payette & Martin Holcik & Arnim Pause & Stephen Lee, 2012. "An oxygen-regulated switch in the protein synthesis machinery," Nature, Nature, vol. 486(7401), pages 126-129, June.
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