The Negative Cross-Talk between SAG/RBX2/ROC2 and APC/C E3 Ligases in Regulation of Cell Cycle Progression and Drug Resistance

Anaphase-promoting complex/cyclosome (APC/C) is a well-characterized E3 ligase that couples with UBE2C and UBE2S E2s for substrate ubiquitylation by the K11 linkage. Our recent data show that SAG/RBX2/ROC2, a RING component of Cullin-RING E3 ligase, also complexes with these E2s for K11-linked substrate polyubiquitylation. Whether these two E3s cross-talk with each other was previously unknown. Here, we report that SAG competes with APC2 for UBE2C/UBE2S binding to act as a potential endogenous inhibitor of APC/C, thereby regulating the G2-to-M progression. As such, SAG knockdown triggers premature activation of APC/C, leading to mitotic slippage and resistance to anti-microtubule drugs. On the other hand, SAG itself is a substrate of APC/C-CDH1 for targeted degradation at the G1 phase. The degradation-resistant mutant of SAG-R98A/L101A accelerates the G1 -to-S progression. Our study reveals that the negative cross-talk between SAG and APC/C is likely a mechanism to ensure the fidelity of cell cycle progression.