SCF^SKP2 regulates APC/C^CDH1-mediated degradation of CTIP to adjust DNA-end resection in G₂-phase.

ABSTRACT: 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 G₁- and G₂-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 G₂-phase specific and is not observed in S-phase or G₁-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 G₂-phase.

SUBMITTER: Li F 

PROVIDER: S-EPMC7368859 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature