Ribonucleotide Metabolism and DNA Damage Response

Ribonucleotide metabolism governs the synthesis of deoxyribonucleoside triphosphates (dNTPs), the building blocks of DNA, and is central to genome replication and repair. The rate-limiting enzyme, ribonucleotide reductase (RNR), catalyses the reduction of ribonucleotides to dNTPs, ensuring a balanced pool that permits high-fidelity DNA synthesis. Imbalances in dNTP concentrations provoke replication stress, stall replication forks and increase the likelihood of misincorporation, leading to genome instability. In response to DNA lesions, cells activate intricate DNA damage response (DDR) pathways, engaging checkpoint kinases that both halt cell cycle progression and upregulate nucleotide synthesis to facilitate repair. Crosstalk between metabolic enzymes and DDR factors ensures that repair processes have sufficient substrate while guarding against oxidative damage. Dysregulation of this interplay underpins a spectrum of pathologies: elevated mutation rates contribute to oncogenesis, whereas insufficient nucleotide supply impairs tissue renewal and immune function. Understanding the regulatory networks linking ribonucleotide metabolism to DDR has yielded new targets for chemotherapeutics and informed strategies to exploit metabolic vulnerabilities in cancer and infectious disease.

Research from Nature Portfolio

Investigations into nucleotide balance have revealed that excess supply of a single nucleotide can disrupt DNA replication without immediate detection by canonical growth pathways. Cells encountering imbalanced dNTP pools activate ATR-dependent replication stress signalling during S phase, which in turn promotes nucleotide availability and maintains fork progression. This work underscores replication stress pathways as critical sensors of metabolic aberrations rather than mTORC1 or AMPK. In parallel, studies of a conserved ester hydrolase, C11orf54, have demonstrated its role in safeguarding homologous recombination repair. Loss of C11orf54 enhances chaperone-mediated autophagy of HIF1A, reducing transcription of the RNR regulatory subunit RRM2 and lowering dNTP levels. Restoration of dNTP pools rescues repair defects and cell survival, revealing a novel link between protein turnover, nucleotide supply and DNA damage tolerance.

Ribonucleotide Metabolism and DNA Damage Response publication trend

The graph below shows the total number of articles in ribonucleotide metabolism and dna damage response across all publications each year (not limited to Nature Index journals).

Technical terms

Ribonucleotide reductase (RNR): Enzyme complex that converts ribonucleotides into deoxyribonucleotides, controlling dNTP supply for DNA synthesis.

Deoxynucleoside triphosphates (dNTPs): Activated deoxyribonucleosides required for DNA replication and repair.

Replication stress: Cellular state in which DNA replication is impeded, leading to fork stalling and genome instability.

Homologous recombination repair (HRR): High-fidelity pathway that repairs DNA double-strand breaks using a homologous template.

Chaperone-mediated autophagy (CMA): Selective degradation pathway in which cytosolic proteins are delivered to lysosomes for breakdown.

ATR signalling: Checkpoint kinase pathway activated by single-stranded DNA regions at stalled forks to coordinate repair and nucleotide synthesis.

References

1. Altered dNTP pools accelerate tumor formation in mice. Nucleic Acids Research (2024).
2. A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability. Molecular Systems Biology (2023).
3. C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A. Communications Biology (2023).
4. Nucleotide imbalance decouples cell growth from cell proliferation. Nature Cell Biology (2022).
5. Implication of Checkpoint Kinase-dependent Up-regulation of Ribonucleotide Reductase R2 in DNA Damage Response*. Journal of Biological Chemistry (2009).