Abstract
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.
Highlights
The sirtuin family has seven members, which are NAD+-dependent protein deacetylases and/or mono-ADPribosyl transferases
SIRT6 overexpression was reported to induce apoptosis and cell d eath[11], we noticed that there were more mitotic cells in SIRT6 overexpressing cells, indicating that SIRT6 overexpression caused cell cycle arrest. To further examine this phenomenon, western blotting was carried out and showed that SIRT6 overexpression led to the elevation of G2/M marker cyclin B1 and phosphorylation of histone H3 at Ser[10], a marker of chromosome condensation during mitosis, indicating arrest in the M phase in SIRT6 overexpressing cells (Fig. 1b)
The results showed that CDC20 and CDH1 overexpression led to an increase in SIRT6 ubiquitination compared with empty vehicle (Fig. 4c, quantification of Ub shown in Supplementary Fig. S6), demonstrating that CDC20 and CDH1 overexpression enhances the ubiquitination of SIRT6
Summary
The sirtuin family has seven members, which are NAD+-dependent protein deacetylases and/or mono-ADPribosyl transferases. The earliest study reported that SIRT6 expression fluctuated during mitosis and that SIRT6 was co-localized with mitotic spindles, indicating that SIRT6 is regulated during this process and there are non-histone substrates of SIRT64. As an E3 ubiquitin ligase that plays a pivotal role in cell cycle progression, the anaphase-promoting complex/ cyclosome (APC/C) is a candidate SIRT6 regulator. Disruption of APC/C regulation may cause serious mitotic deficiency and lead to genomic instability, which has been associated with the initiation of different types of cancer. SIRT6 deacetylates CDH1 at K135, which promotes degradation of CDH1, reducing APC/C-CDH1 E3 ligase activity. Through this process, overexpression of SIRT6 leads to upregulation of a number of APC/C substrates, resulting in mitotic defects and genome instability
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