SCF(SKP2) regulates APC/C(CDH1)-mediated degradation of CTIP to adjust DNA-end resection in G(2)-phase

The cell cycle-dependent engagement of DNA-end resection at DSBs is regulated by phosphorylation of CTIP by CDKs, the central regulators of cell cycle transitions. Cell cycle transitions are also intimately regulated by protein degradation via two E3 ubiquitin ligases: SCF(SKP2) and APC/C(CDH1) complex. Although APC/C(CDH1) regulates CTIP in G(1)– and G(2)-phase, contributions by SCF(SKP2) have not been reported. We demonstrate that SCF(SKP2) is a strong positive regulator of resection. Knockdown of SKP2, fully suppresses resection in several cell lines. Notably, this suppression is G(2)-phase specific and is not observed in S-phase or G(1)–phase cells. Knockdown of SKP2 inactivates SCF(SKP2) causing APC/C(CDH1) activation, which degrades CTIP. The stabilizing function of SCF(SKP2) on CTIP promotes resection and supports gene conversion (GC), alternative end joining (alt-EJ) and cell survival. We propose that CDKs and SCF(SKP2)-APC/C(CDH1) cooperate to regulate resection and repair pathway choice at DSBs in G(2)-phase.