Altered dNTP pools accelerate tumor formation in mice

Area of Science:

• Biochemistry
• Genetics
• Oncology

Background:

• Alterations in deoxyribonucleoside triphosphate (dNTP) pools are associated with increased mutation rates and genome instability.
• The specific role of dNTP pool changes in mammalian tumor development is not well understood.

Purpose of the Study:

• To investigate the impact of altered dNTP pools on tumor development in mammals.
• To establish a mouse model mimicking impaired dNTP synthesis.

Main Methods:

• Created a mouse model with a point mutation (RRM1-Y285A) in ribonucleotide reductase.
• Analyzed dNTP pool alterations across organs in heterozygous Rrm1+/Y285A mice.
• Performed mutational spectrum analysis on tumors from these mice.

Main Results:

• The RRM1-Y285A mutation reduced ribonucleotide reductase activity, decreasing deoxyadenosine triphosphate (dATP) and deoxyguanosine triphosphate (dGTP) synthesis.
• Heterozygous mice showed altered dNTP pools, reduced lifespan, and earlier tumor onset compared to wild-type controls.
• Tumor mutational analysis revealed signatures similar to human cancers with related mutations.

Conclusions:

• Mutations in dNTP metabolism enzymes can drive cancer development.
• Altered dNTP pools contribute to genome instability and tumorigenesis in mammals.
• The RRM1-Y285A mouse model provides insights into cancer mechanisms driven by dNTP pool imbalances.