Disruption of deoxyribonucleotide triphosphate biosynthesis leads to RAS proto-oncogene activation and perturbation of mitochondrial metabolism
Perturbation of the deoxyribonucleotide triphosphate (dNTP) pool is recognized for contributing to the mutagenic processes involved in oncogenesis. The RAS gene family encodes well-characterized oncoproteins whose structure and function are among the most frequently altered in several cancers. In this work, we show that fluctuation of the dNTP pool induces CG → TA mutations across the whole genome, including RAS gene at codons for glycine 12 and 13, known hotspots in cancers. Cell culture addition of the ribonucleotide reductase inhibitor thymidine increases the mutation frequency in nuclear DNA and leads to disruption of mitochondrial metabolism. Interestingly, this effect is counteracted by the addition of deoxycytidine. Finally, screening for the loss of hydrogen bonds detecting CG → TA transition in RAS gene of 135 patients with colorectal cancer confirmed the clinical relevance of this process. All together, these data demonstrate that fluctuation of intracellular dNTP pool alters the nuclear DNA and mitochondrial metabolism.
Authors
- Rodolphe Suspène
- Jean‐Pierre Vartanian (ORCID: https://orcid.org/0000-0001-8079-8814)
- Pablo Guardado‐Calvo (ORCID: https://orcid.org/0000-0001-7292-5270)
- Kyle A. Raymond (ORCID: https://orcid.org/0000-0001-8670-2852)
- Frédéric Bonhomme (ORCID: https://orcid.org/0000-0001-6797-289X)
- Julien Dairou (ORCID: https://orcid.org/0000-0003-1767-0572)
- Jean‐Christophe Pagès (ORCID: https://orcid.org/0000-0002-6852-5546)
- Serge Guyétant (ORCID: https://orcid.org/0000-0003-2783-9722)
- Thierry Lecomte (ORCID: https://orcid.org/0000-0001-5093-0212)
- Christine Bonenfant
Institutions
- Université de Tours (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Pasteur (FR)
- École Nationale Vétérinaire de Toulouse (FR)
- Université Fédérale de Toulouse Midi-Pyrénées (FR)
- Université Paris Cité (FR)
- Sorbonne Université (FR)
- Centre Hospitalier Universitaire de Tours (FR)
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (FR)
- Thion Medical (France) (FR)
- Epigénétique et Destin Cellulaire (FR)
- Hôpital Purpan (FR)
Publication Details
- Journal
- Journal of Biological Chemistry
- Published
- 2024-12-23
- DOI
- https://doi.org/10.1016/j.jbc.2024.108117
- Citations
- 1
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 0.29
Funders
- Infrastructures en Biologie Santé et Agronomie
- Agence Nationale de la Recherche