Interaction Between SIRT6 And The Anaphase-Promoting Complex/Cyclosome Regulates Cell Cycle

SIRT6 is an NAD~+-dependent deacetylase and plays important role in mitosis/meiosis fidelity and genome stability,while the regulation of SIRT6 during mitosis and its downstream substrate is not yet clearly elucidated.In the present work,we found that SIRT6 aberration leads to various mitosis defects and aneuploidy.We identified that SIRT6 was 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 ubiquitination.Reciprocally,SIRT6 also deacetylates CDH1 at K135,leading to its degradation and an increase of APC/C-CDH1-targeted substrates,resulting in dysfunction of multiple cellular processes,including centrosome amplification and chromosome stability.Taken it together,our findings demonstrate the importance of SIRT6 for maintaining genome integrity during mitotic progression and reveal how SIRT6 and APC/C cooperate to drive mitosis.