Production of deoxyribonucleotide triphosphates (dNTPs) is essential for DNA synthesis during replication and repair, and abnormal or imbalanced dNTP levels increases mutation frequency. Pagano and colleagues now demonstrate that the SCF-cyclin F ubiquitin ligase controls dNTP production during the cell cycle and following genotoxic stress (Cell 149, 1023–1034; 2012).

The authors identify the ribonucleotide reductase subunit RRM2 as a cyclin-F-interacting protein using mass spectrometry, and find that the two proteins interact specifically in the G2 and M phases of the cell cycle. Cyclin F binds RRM2 in a manner dependent on an RRM2 CY motif and on Cdk1- or Cdk2-mediated phosphorylation of Thr 33 in RRM2, and mediates its degradation by the proteasome. Depletion of cyclin F or expression of stable RRM2 mutants increases the amount of dATP and dGTP (but not of dCTP or dTTP). Further, cell clones expressing these stabilized RRM2 mutants show an increase in the mutation frequency of a reporter gene.

RRM2 is known to accumulate in the nucleus following DNA damage, to provide dNTPs for repair. Interestingly, the authors find that various DNA-damaging agents downregulate cyclin F levels (dependent on the ATR kinase), and demonstrate that this is required for efficient DNA repair. These data underscore the importance of maintaining sufficient and balanced dNTP pools, and provide mechanistic insights into how this is achieved.