Cyclin F-Mediated Degradation of Ribonucleotide Reductase M2 Controls Genome Integrity and DNA Repair

F-box proteins are the substrate binding subunits of SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complexes. Using affinity purifications and mass spectrometry, we identified RRM2 (the ribonucleotide reductase family member 2) as an interactor of the F-box protein cyclin F. Ribonucleotide reductase (RNR) catalyzes the conversion of ribonucleotides to deoxyribonucleotides (dNTPs), which are necessary for both replicative and repair DNA synthesis. We found that, during G2, following CDK-mediated phosphorylation of Thr33, RRM2 is degraded via SCFcyclin F to maintain balanced dNTP pools and genome stability. After DNA damage, cyclin F is downregulated in an ATR-dependent manner to allow accumulation of RRM2. Defective elimination of cyclin F delays DNA repair and sensitizes cells to DNA damage, a phenotype that is reverted by expressing a nondegradable RRM2 mutant. In summary, we have identified a biochemical pathway that controls the abundance of dNTPs and ensures efficient DNA repair in response to genotoxic stress. [Display omitted] ► In G2, cyclin F promotes degradation of phosphorylated ribonucleotide reductase M2 ► Degradation of RRM2 maintains a balanced pool of dNTPs and genome stability ► In response to DNA damage, cyclin F is eliminated in a ATR-dependent manner ► Cyclin F elimination allows accumulation of RRM2 for efficient DNA repair Modulation of the levels of an enzyme that converts ribonucleotides into deoxyribonucleotides ensures the availability of dNTPs for DNA replication and repair, providing a mechanism to protect cells from genotoxic stress and promote genomic integrity.