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

Authors :
Yi Sun
Xiufang Xiong
Yilun Sun
Chao Bi
Wenyi Wei
Yanwen Shen
Shizhen Zhang
Hua Li
Source :
SSRN Electronic Journal.
Publication Year :
2020
Publisher :
Elsevier BV, 2020.

Abstract

APC/C is a well characterized E3 ligase that couples with UBE2C and UBE2S E2s for ubiquitylation of the targeted substrates via the K11 linkage. Our recent data showed that SAG/RBX2/ROC2, a RING component of Cullin-RING E3 ligase (CRL), also complexes with these two E2s (UBE2C/2S) for K11-linked substrate polyubiquitylation. Whether these two E3s cross-talk with each other and the associated biological consequence are previously unknown. Here we report that these two E3s inhibit each other during cell cycle progression, which could lead to drug resistance. Specifically, SAG competes with APC2 for UBE2C/UBE2S binding to act as an endogenous inhibitor of APC/C, thereby regulating the G2/M progression. SAG inactivation triggers premature activation of APC/C, leading to mitotic slippage, as well as the resistance of cancer cells to anti-microtubule drugs both in vitro and in vivo models. On the other hand, SAG itself is a substrate of APC/CCDH1 for targeted degradation at the G1 phase. The degradation-resistant mutant of SAG-R82A/L85A accelerates the G1 to S progression, thereby promoting proliferation/survival of lung cancer cells. Our study reveals that the negative crosstalk between SAG and APC/C is likely a mechanism to ensure the fidelity of cell cycle progression, and manipulations to abrogate this fine balance would lead to enhanced proliferation and drug resistance.

Details

ISSN :
15565068
Database :
OpenAIRE
Journal :
SSRN Electronic Journal
Accession number :
edsair.doi...........c3f2d6fc671d822e7d2dc6103a811d73
Full Text :
https://doi.org/10.2139/ssrn.3544931