Reciprocal Regulation between 53BP1 and the Anaphase-Promoting Complex/Cyclosome Is Required for Genomic Stability during Mitotic Stress
Reciprocal Regulation between 53BP1 and the Anaphase-Promoting Complex/Cyclosome Is Required for Genomic Stability during Mitotic Stress
复制标题
DOI：
10.1016/j.celrep.2017.01.080
复制
发表时间：
2017-02-21
期刊：
影响因子：
8.8
通讯作者：
Teodoro, Jose G.
中科院分区：
文献类型：
--
作者：
Kucharski, Thomas J.;Minshall, Paul E.;Teodoro, Jose G.
后期促进复合体/环体(APC/C)是一种E3泛素连接酶，针对底物进行降解以促进有丝分裂进程。在这里，我们证明了DNA损伤反应蛋白53BP1包含保守的KEN盒，这是有丝分裂早期依赖APC/C降解所必需的。53BP1 Ken盒的突变稳定了蛋白质，延长了有丝分裂持续时间，而53BP1基因敲除导致有丝分裂缩短和延迟。53BP1的缺失增加了APC/C的活性，我们证明53BP1是一种直接的APC/C抑制物。虽然53BP1功能对正常的细胞周期进程并不是绝对必需的，但基因敲除与有丝分裂纺锤体毒药结合在一起具有很高的毒性。此外，化学抑制APC/C能够挽救53BP1丢失的致死性。我们的发现揭示了53BP1和APC/C之间的相互调节，这是响应有丝分裂应激所必需的，可能有助于53BP1的肿瘤抑制功能。
The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets substrates for degradation to promote mitotic progression. Here, we show that the DNA damage response protein 53BP1 contains conserved KEN boxes that are required for APC/C-dependent degradation in early mitosis. Mutation of the 53BP1 KEN boxes stabilized the protein and extended mitotic duration, whereas 53BP1 knockdown resulted in a shorter and delayed mitosis. Loss of 53BP1 increased APC/C activity, and we show that 53BP1 is a direct APC/C inhibitor. Although 53BP1 function is not absolutely required for normal cell cycle progression, knockdown was highly toxic in combination with mitotic spindle poisons. Moreover, chemical inhibition of the APC/C was able to rescue the lethality of 53BP1 loss. Our findings reveal a reciprocal regulation between 53BP1 and APC/C that is required for response to mitotic stress and may contribute to the tumor-suppressor functions of 53BP1.