The treatment of disorders caused by defective dNTP metabolism

dNTPs are the building blocks of DNA and are required for genome duplication during cell division.

Less well known is that dNTPs also have essential functions in non-dividing cells, where they are used for replication of mitochondrial DNA and repair of nuclear DNA.

The concentration of dNTPs in non-dividing cells is controlled by three processes: de novo synthesis, degradation, and salvage.

Disturbances in these processes lead to abnormal dNTP pools and to severe human diseases that currently lack treatment.The purpose of this project is to find means of restoring normal dNTP pools in patients with defective dNTP metabolism.

The aims of the project are to understand (i) the interplay between de novo synthesis, degradation, and salvage of dNTPs in non-dividing cells, (ii) how defects in these processes affect the stability of nuclear and mitochondrial genomes, and (iii) whether abnormal dNTP pools in mice with mutations in the dNTP-synthesizing enzymes can be restored by exogenously supplied dNTP precursors (deoxyribonucleosides).

To achieve these aims, four researchers in my group will use an integrated approach combining biochemistry (years 1–3), cell biology (years 1–4), and animal studies (years 1–5).Achieving these aims will have important implications for understanding how defects in dNTP metabolism in non-dividing cells cause human disease and will hopefully lead to new treatment therapies for rare diseases caused by abnormal dNTP pools.