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RPL22L1-dependent translational control of DNA repair confers chemoresistance

ABSTRACT: Ribosome heterogeneity has emerged as a regulatory layer in gene expression, yet its biological roles in cancers remain poorly understood. Here, we identify RPL22L1, a paralog of the ribosomal protein RPL22, as a key modulator of DNA damage response (DDR) in colorectal cancer cells. DNA damage induces RPL22L1 upregulation and ribosomal incorporation, forming RPL22L1-containing ribosomes. Ribosome profiling revealed that RPL22L1-containing ribosomes preferentially translate mRNAs with highly structured 5’ untranslated region (5’UTR). In particular, RPL22L1 enhances the translation of ATRX through an internal ribosome entry site (IRES)-dependent mechanism. ATRX subsequently recruits DNA-PKcs to DNA damage sites, thereby enhancing the non-homologous end joining (NHEJ) activity. RPL22L1 loss creates exploitable DDR vulnerabilities, sensitizing cancer cells to cisplatin and PARP inhibitors in vitro and in vivo. Collectively, these findings uncover a specialized ribosome-mediated translational program in DDR and highlight RPL22L1 as a potential therapeutic target in DNA damage-based cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310281 | GEO | 2026/06/21

REPOSITORIES: GEO

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