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Disruption of deoxyribonucleotide triphosphate biosynthesis leads to RAS proto-oncogene activation and perturbation

Rodolphe Suspène1, Kyle A Raymond2, Pablo Guardado-Calvo3

  • 1Virus and Cellular Stress Unit, Department of Virology, Université Paris Cité, Institut Pasteur, Paris, France.

The Journal of Biological Chemistry
|December 26, 2024
PubMed

Insights

Altering deoxyribonucleotide triphosphate (dNTP) pools causes specific DNA mutations in cancer genes like RAS. This impacts nuclear DNA and mitochondrial metabolism, with clinical relevance in colorectal cancer.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Perturbation of deoxyribonucleotide triphosphate (dNTP) pools is linked to oncogenesis.
  • The RAS gene family is frequently altered in various cancers.

Purpose of the Study:

  • To investigate how dNTP pool fluctuations induce specific mutations, particularly CG → TA transitions.
  • To explore the impact of these mutations on RAS genes and mitochondrial metabolism.
  • To confirm the clinical relevance of these findings in colorectal cancer patients.

Main Methods:

  • Utilized cell culture models to study dNTP pool alterations.
  • Administered thymidine (ribonucleotide reductase inhibitor) and deoxycytidine.
  • Analyzed mutation frequencies in nuclear DNA and mitochondrial metabolism.
  • Screened RAS genes from colorectal cancer patients for CG → TA transitions.

Main Results:

  • dNTP pool fluctuations induce CG → TA mutations genome-wide, including RAS hotspots.
  • Thymidine treatment increased mutation frequency and disrupted mitochondrial metabolism.
  • Deoxycytidine addition counteracted these effects.
  • Clinical screening confirmed CG → TA transitions in RAS genes of colorectal cancer patients.

Conclusions:

  • Intracellular dNTP pool fluctuations drive specific DNA mutations and alter mitochondrial metabolism.
  • These findings highlight a novel mechanism in cancer development and progression.
  • Targeting dNTP pools may offer new therapeutic strategies for cancer treatment.
Keywords:
DNARAS genecancermitochondriamutationnucleotide

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