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

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• 作者：Vincenzo D'Angiolella¹ ; Valerio Donato¹ ; Frances&#160 ; M. Forrester¹ ; Yeon-Tae Jeong¹ ; Claudia Pellacani¹ ; Yasusei Kudo¹ ; ² ; Anita Saraf³ ; Laurence Florens³ ; Michael&#160 ; P. Washburn³ ; ⁴ ; Michele Pagano¹ ; ⁵ ; ^{michele.pagano@nyumc.org}
• 刊名：Cell
• 出版年：2012
• 期刊代码：50_00928674
• 类别：med
• 出版时间：25 May, 2012
• 卷：149
• 期：5
• 页码：1023-1034
• 文件大小：1779 K

摘要

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Summary

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聽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.