Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.
Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, 4424B MS-1, 1301 Catherine Street, Ann Arbor, MI 48109, USA.
Cell Rep. 2020 Sep 8;32(10):108102. doi: 10.1016/j.celrep.2020.108102.
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 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/环体（APC/C）是一种特征明确的 E3 连接酶，它与 UBE2C 和 UBE2S E2 结合，通过 K11 连接使底物泛素化。我们最近的数据表明，SAG/RBX2/ROC2，一种 Cullin-RING E3 连接酶的 RING 成分，也与这些 E2 结合，进行 K11 连接的底物多泛素化。这两个 E3 是否相互作用以前是未知的。在这里，我们报告说 SAG 与 APC2 竞争 UBE2C/UBE2S 的结合，作为 APC/C 的潜在内源性抑制剂，从而调节 G2 到 M 的进展。因此，SAG 敲低会触发 APC/C 的过早激活，导致有丝分裂滑步和对微管药物的耐药性。另一方面，SAG 本身是 APC/C 的一个底物，在 G1 期被靶向降解。SAG-R98A/L101A 的降解抗性突变加速了 G1 到 S 的进展。我们的研究表明，SAG 和 APC/C 之间的负性相互作用可能是确保细胞周期进程保真度的一种机制。
