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.

后期促进复合物/细胞周期体 (APC/C) 是一种充分表征的 E3 连接酶，可与 UBE2C 和 UBE2S E2 结合，通过 K11 连接进行底物泛素化。我们最近的数据表明，SAG/RBX2/ROC2 是 Cullin-RING E3 连接酶的 RING 组分，也与这些 E2 复合以进行 K11 连接的底物多泛素化。这两个 E3 是否相互串扰以前是未知的。在这里，我们报告说 SAG 与 APC2 竞争 UBE2C/UBE2S 结合，作为 APC/C 的潜在内源性抑制剂，从而调节 G2-to-M 进程。因此，SAG 敲低会触发 APC/C 的过早激活，导致有丝分裂滑动和抗微管药物耐药。另一方面，SAG本身是APC/C ^{CDH1的底物}在 G1 阶段有针对性地降解。SAG-R98A/L101A 的抗降解突变体加速了 G1 到 S 的进程。我们的研究表明，SAG 和 APC/C 之间的负串扰可能是确保细胞周期进程保真度的一种机制。