Harnessing DNA replication stress to target RBM10 deficiency in lung adenocarcinoma

Feras E. Machour, Enas R. Abu-Zhayia, Joyce Kamar, Alma Sophia Barisaac, Itamar Simon and Nabieh Ayoub ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50882-0

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