Kucharski Thomas J, Minshall Paul E, Moustafa-Kamal Mohamed, Turnell Andrew S, Teodoro Jose G
Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
School of Cancer and Genomic Sciences, College of Medical and Dental Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Cell Rep. 2017 Feb 21;18(8):1982-1995. doi: 10.1016/j.celrep.2017.01.080.
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.
后期促进复合物/细胞周期体（APC/C）是一种E3泛素连接酶，它靶向底物进行降解以促进有丝分裂进程。在此，我们表明DNA损伤反应蛋白53BP1含有保守的KEN框，这些框是有丝分裂早期APC/C依赖性降解所必需的。53BP1的KEN框发生突变会使该蛋白稳定并延长有丝分裂持续时间，而敲低53BP1则导致有丝分裂缩短和延迟。53BP1的缺失增加了APC/C的活性，并且我们表明53BP1是一种直接的APC/C抑制剂。虽然正常细胞周期进程并非绝对需要53BP1发挥功能，但敲低53BP1与有丝分裂纺锤体毒物联合使用时具有高度毒性。此外，对APC/C的化学抑制能够挽救53BP1缺失所导致的致死性。我们的研究结果揭示了53BP1与APC/C之间的相互调节，这是应对有丝分裂应激所必需的，并且可能有助于53BP1的肿瘤抑制功能。
