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Ribosomal RNA 2′O-methylation as a novel layer of inter-tumour heterogeneity in breast cancer

Virginie Marcel 1, * Janice Kielbassa 2 Virginie Marchand 3 Kundhavai s Natchiar 4 Hermes Paraqindes 1, 2 Flora Nguyen van long 1 Lilia Ayadi 3, 5 Valérie Bourguignon-Igel 3, 5 Piero Lo monaco 1 Déborah Monchiet 1 Véronique Scott 6 Laurie Tonon 2 Susan Bray 7 Alexandra Diot 7 Lee Jordan 7 Alastair Thompson 7, 8 Jean-Christophe Bourdon 7 Thierry Dubois 9 Fabrice André 6 Frédéric Catez 1 Alain Puisieux 1 Yuri Motorin 3, 5 Bruno  Klaholz 4 Alain Viari 2, 10 Jean-Jacques Diaz 1
* Corresponding author
1 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
2 Synergie Lyon Cancer-Platform of Bioinformatics-Gilles Thomas
UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
3 IBSLor - Ingénierie, Biologie et Santé en Lorraine
4 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
5 IMoPA - Ingénierie Moléculaire et Physiopathologie Articulaire
6 PMNCO - Prédicteurs moléculaires et nouvelles cibles en oncologie
7 Ninewells Hospital and Medical School [Dundee]
8 BCM - Baylor College of Medicine
9 Institut Curie [Paris]
10 Inria Grenoble - Rhône-Alpes
Abstract : Recent epitranscriptomics studies unravelled that ribosomal RNA (rRNA) 2′O-methylation is an additional layer of gene expression regulation highlighting the ribosome as a novel actor of translation control. However, this major finding lies on evidences coming mainly, if not exclusively, from cellular models. Using the innovative next-generation RiboMeth-seq technology, we established the first rRNA 2′O-methylation landscape in 195 primary human breast tumours. We uncovered the existence of compulsory/stable sites, which show limited inter-patient variability in their 2′O-methylation level, which map on functionally important sites of the human ribosome structure and which are surrounded by variable sites found from the second nucleotide layers. Our data demonstrate that some positions within the rRNA molecules can tolerate absence of 2′O-methylation in tumoral and healthy tissues. We also reveal that rRNA 2′O-methylation exhibits intra- and inter-patient variability in breast tumours. Its level is indeed differentially associated with breast cancer subtype and tumour grade. Altogether, our rRNA 2′O-methylation profiling of a large-scale human sample collection provides the first compelling evidence that ribosome variability occurs in humans and suggests that rRNA 2′O-methylation might represent a relevant element of tumour biology useful in clinic. This novel variability at molecular level offers an additional layer to capture the cancer heterogeneity and associates with specific features of tumour biology thus offering a novel targetable molecular signature in cancer.
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https://www.hal.inserm.fr/inserm-03103238
Contributor : Bruno Klaholz <>
Submitted on : Friday, January 8, 2021 - 7:35:15 AM
Last modification on : Wednesday, February 24, 2021 - 11:26:05 AM

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INSERM | IGBMC | CURIE | PSL | FNCLCC | UNIV-LORRAINE | UNIV-LYON1 | IMOPA-UL | CRCL | CNRS | UDL | SITE-ALSACE | IBSLOR-UL | INRIA | BMS-UL | IGR | IMOPA

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Virginie Marcel, Janice Kielbassa, Virginie Marchand, Kundhavai s Natchiar, Hermes Paraqindes, et al.. Ribosomal RNA 2′O-methylation as a novel layer of inter-tumour heterogeneity in breast cancer. NAR Cancer, Oxford University Press, 2020, 2 (4), pp.zcaa036. ⟨10.1093/narcan/zcaa036⟩. ⟨inserm-03103238⟩

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