Loss of SNORD104-guided rRNA methylation promotes early adaptation to crizotinib in lung adenocarcinoma

Abstract The ribosome, long considered an invariant actor of gene expression, recently emerged as a contributor to translational control through chemical modifications of ribosomal RNAs (rRNAs). These modifications are guided by small nucleolar RNAs (snoRNAs), which direct modifying enzymes to specific rRNA positions. Here, we report that lung adenocarcinoma (LUAD) cells that are resistant to tyrosine kinase inhibitors (TKIs) reshape both their translational program and rRNA 2’O-ribose methylation (2’Ome) profiles. EML4-ALK -positive LUAD cells that are resistant to crizotinib (ALK inhibitor) exhibit reduced global protein synthesis and a change in selective translation of mRNAs, encoding proteins previously linked to resistance. These cells show concomitant reduction in SNORD104 and 2’Ome at its associated 28S_Cm1327 position. Functional studies reveal that SNORD104 depletion abolishes 2’Ome at 28S_Cm1327 without affecting basal translation or cell viability, but enhances both under crizotinib exposure. Moreover, SNORD104 knockdown attenuates caspase activation and PARP cleavage during treatment, supporting reduced cell death. Altogether, our findings support a role for snoRNA-guided rRNA modification as a novel non-genomic mechanism in early adaptive responses to crizotinib therapy in LUAD.

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Publication Details

Journal
Cell Death and Disease
Published
2026-08-24
DOI
https://doi.org/10.1038/s41419-026-09160-8
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
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article

Loss of SNORD104-guided rRNA methylation promotes early adaptation to crizotinib in lung adenocarcinoma

Mounira Chalabi‐Dchar, Nour‐El‐Houda Mourksi, Éric Rivals, Frédéric Catez et al.
Cell Death and Disease
RNA modifications and cancer
article

Loss of SNORD104-guided rRNA methylation promotes early adaptation to crizotinib in lung adenocarcinoma

Mounira Chalabi‐Dchar, Nour‐El‐Houda Mourksi, Éric Rivals, Frédéric Catez, Jean‐Jacques Diaz, Chloé Morin, Hermes Paraqindes, Julie Ripoll, Caroline Isaac, Virginie Marchand, Camille Léonce, Laury Baillon, Mariam Jaafar, Rita Khoueiry, Fleur Bourdelais, Virginie Marcel, Déborah Monchiet, Yuri Motorin, Julie Radermecker, Celine MANDIER, Geneviève De Souza, Camille Jouines, Thomas Boyer, Christine M. Lovly, Sandra Ortiz-Cuaran, Pierre Saintigny, Sébastien Durand
article en

Abstract

Abstract The ribosome, long considered an invariant actor of gene expression, recently emerged as a contributor to translational control through chemical modifications of ribosomal RNAs (rRNAs). These modifications are guided by small nucleolar RNAs (snoRNAs), which direct modifying enzymes to specific rRNA positions. Here, we report that lung adenocarcinoma (LUAD) cells that are resistant to tyrosine kinase inhibitors (TKIs) reshape both their translational program and rRNA 2’O-ribose methylation (2’Ome) profiles. EML4-ALK -positive LUAD cells that are resistant to crizotinib (ALK inhibitor) exhibit reduced global protein synthesis and a change in selective translation of mRNAs, encoding proteins previously linked to resistance. These cells show concomitant reduction in SNORD104 and 2’Ome at its associated 28S_Cm1327 position. Functional studies reveal that SNORD104 depletion abolishes 2’Ome at 28S_Cm1327 without affecting basal translation or cell viability, but enhances both under crizotinib exposure. Moreover, SNORD104 knockdown attenuates caspase activation and PARP cleavage during treatment, supporting reduced cell death. Altogether, our findings support a role for snoRNA-guided rRNA modification as a novel non-genomic mechanism in early adaptive responses to crizotinib therapy in LUAD.

Cell Death and Disease
Université Claude Bernard Lyon 1 (FR), École Normale Supérieure de Lyon (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université de Montpellier (FR), Laboratoire d'Informatique, de Robotique et de Microélectronique de Montpellier (FR), Centre Léon Bérard (FR), City of Hope (US), Centre de Recherche en Cancérologie de Lyon (FR), Centre international de recherche sur le cancer (FR), Université de Lorraine (FR)
Good health and well-being
Openalex Percentile: Top 16%
RNA modifications and cancer
DOIOpen Access PDFOpenAlex
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