MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, 100043, China.
Sci Rep. 2021 Jul 9;11(1):14253. doi: 10.1038/s41598-021-93684-w.
SIRT6 is an NAD-dependent deacetylase that plays an important role in mitosis fidelity and genome stability. In the present study, we found that SIRT6 overexpression leads to mitosis defects and aneuploidy. We identified SIRT6 as a novel substrate of anaphase-promoting complex/cyclosome (APC/C), which is a master regulator of mitosis. Both CDH1 and CDC20, co-activators of APC/C, mediated SIRT6 degradation via the ubiquitination-proteasome pathway. Reciprocally, SIRT6 also deacetylated CDH1 at lysine K135 and promoted its degradation, resulting in an increase in APC/C-CDH1-targeted substrates, dysfunction in centrosome amplification, and chromosome instability. Our findings demonstrate the importance of SIRT6 for genome integrity during mitotic progression and reveal how SIRT6 and APC/C cooperate to drive mitosis.
SIRT6 是一种依赖 NAD 的去乙酰化酶，在有丝分裂保真度和基因组稳定性中发挥重要作用。在本研究中，我们发现 SIRT6 的过表达会导致有丝分裂缺陷和非整倍体。我们鉴定出 SIRT6 是后期促进复合物/周期蛋白（APC/C）的一种新型底物，APC/C 是有丝分裂的主要调控因子。APC/C 的共同激活因子 CDH1 和 CDC20 通过泛素蛋白酶体途径介导 SIRT6 的降解。反过来，SIRT6 还在赖氨酸 K135 处使 CDH1 去乙酰化，并促进其降解，导致 APC/C-CDH1 靶向底物增加、中心体扩增功能障碍和染色体不稳定。我们的研究结果表明 SIRT6 在有丝分裂进程中对基因组完整性的重要性，并揭示了 SIRT6 和 APC/C 如何合作以推动有丝分裂。
