Loss of SNORD104-guided rRNA methylation promotes early adaptation to crizotinib in lung adenocarcinoma
Year: 2026
Type: article
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.
Source: Cell Death and Disease
Authors: Nour-El-Houda Mourksi, Caroline Isaac, Julie Ripoll, Julie Radermecker, Chloé Morin, Geneviève De Souza, Camille Léonce, Hermes Paraqindes, Camille Jouines, Thomas Boyer, Déborah Monchiet, Laury Baillon, Mariam Jaafar, Mounira Chalabi-Dchar, Frédéric Catez, Sébastien Durand, Céline Mandier, Virginie Marchand, Yuri Motorin, Fleur Bourdelais, Rita Khoueiry, Christine M. Lovly, Pierre Saintigny, Eric Rivals, Sandra Ortiz-Cuaran, Jean-Jacques Diaz, Virginie Marcel
Institutions: Lyon 1 Université, Centre National de la Recherche Scientifique, Inserm, Université de Lyon, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université de Montpellier, Laboratoire d'Informatique, de Robotique et de Microélectronique de Montpellier, École Normale Supérieure de Lyon, Institut national de recherche en sciences et technologies du numérique, CASTING: Dynamiques du Cancer, adaptation et modélisation, Université de Lorraine, Ingénierie Moléculaire, Cellulaire et Physiopathologie, Centre international de recherche sur le cancer, City Of Hope National Medical Center
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,990
OpenAlex ID: W7204141789
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