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Harnessing DNA replication stress to target RBM10 deficiency in lung adenocarcinoma

Author

Listed:
  • Feras E. Machour

    (Technion—Israel Institute of Technology)

  • Enas R. Abu-Zhayia

    (Technion—Israel Institute of Technology)

  • Joyce Kamar

    (The Hebrew University)

  • Alma Sophia Barisaac

    (Technion—Israel Institute of Technology)

  • Itamar Simon

    (The Hebrew University)

  • Nabieh Ayoub

    (Technion—Israel Institute of Technology)

Abstract

The splicing factor RNA-binding motif protein 10 (RBM10) is frequently mutated in lung adenocarcinoma (LUAD) (9-25%). Most RBM10 cancer mutations are loss-of-function, correlating with increased tumorigenesis and limiting the efficacy of current LUAD targeted therapies. Remarkably, therapeutic strategies leveraging RBM10 deficiency remain unexplored. Here, we conduct a CRISPR-Cas9 synthetic lethality (SL) screen and identify ~60 RBM10 SL genes, including WEE1 kinase. WEE1 inhibition sensitizes RBM10-deficient LUAD cells in-vitro and in-vivo. Mechanistically, we identify a splicing-independent role of RBM10 in regulating DNA replication fork progression and replication stress response, which underpins RBM10-WEE1 SL. Additionally, RBM10 interacts with active DNA replication forks, relying on DNA Primase Subunit 1 (PRIM1) that synthesizes Okazaki RNA primers. Functionally, we demonstrate that RBM10 serves as an anchor for recruiting Histone Deacetylase 1 (HDAC1) to facilitate H4K16 deacetylation and R-loop homeostasis to maintain replication fork stability. Collectively, our data reveal a role of RBM10 in fine-tuning DNA replication and provide therapeutic arsenal for targeting RBM10-deficient tumors.

Suggested Citation

  • Feras E. Machour & Enas R. Abu-Zhayia & Joyce Kamar & Alma Sophia Barisaac & Itamar Simon & Nabieh Ayoub, 2024. "Harnessing DNA replication stress to target RBM10 deficiency in lung adenocarcinoma," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50882-0
    DOI: 10.1038/s41467-024-50882-0
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    References listed on IDEAS

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    1. Philippe Coulombe & Joelle Nassar & Isabelle Peiffer & Slavica Stanojcic & Yvon Sterkers & Axel Delamarre & Stéphane Bocquet & Marcel Méchali, 2019. "The ORC ubiquitin ligase OBI1 promotes DNA replication origin firing," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    2. Roy S. Herbst & Daniel Morgensztern & Chris Boshoff, 2018. "The biology and management of non-small cell lung cancer," Nature, Nature, vol. 553(7689), pages 446-454, January.
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