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 SCF(cyclin 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.
Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA.
Vincenzo
V
D'Angiolella
Valerio
V
Donato
Frances M
FM
Forrester
Yeon-Tae
YT
Jeong
Claudia
C
Pellacani
Yasusei
Y
Kudo
Anita
A
Saraf
Laurence
L
Florens
Michael P
MP
Washburn
Michele
M
Pagano
D020816:Amino Acid Motifs; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D015536:Down-Regulation; D016195:G2 Phase; D042822:Genomic Instability; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012262:Ribonucleoside Diphosphate Reductase / Q000378:metabolism*
C503669:CCNF protein, human; D018797:Cell Cycle Proteins; D016213:Cyclins; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases