Centrosome dysfunction associated with somatic expression of the synaptonemal complex protein TEX12

The synaptonemal complex (SC) is a supramolecular protein scaffold that mediates chromosome synapsis and facilitates crossing over during meiosis. In mammals, SC proteins are generally assumed to have no other function. Here, we show that SC protein TEX12 also localises to centrosomes during meiosis independently of chromosome synapsis. In somatic cells, ectopically expressed TEX12 similarly localises to centrosomes, where it is associated with centrosome amplification, a pathology correlated with cancer development. Indeed, TEX12 is identified as a cancer-testis antigen and proliferation of some cancer cells is TEX12-dependent. Moreover, somatic expression of TEX12 is aberrantly activated via retinoic acid signalling, which is commonly disregulated in cancer. Structure-function analysis reveals that phosphorylation of TEX12 on tyrosine 48 is important for centrosome amplification but not for recruitment of TEX12 to centrosomes. We conclude that TEX12 normally localises to meiotic centrosomes, but its misexpression in somatic cells can contribute to pathological amplification and dysfunction of centrosomes in cancers.

The Binding Between ROCK1 and KIF2A Signals for the Centrosome Amplification Triggered by High Glucose, Insulin and Palmitic Acid

Diabetes increases the risk for various cancers without established mechanisms. Centrosome amplification can initiate tumorigenesis in genetically modified cells. However, the findings from genetically modified experimental models may be far away from reality. We have reported that diabetes promotes the occurrence of centrosome amplification in different types of cells, implicating that centrosome amplification is a candidate mechanism underlying the diabetes-promoted tumorigenesis. In the present study, we investigated the molecular mechanisms of the centrosome amplification triggered by high glucose, insulin and palmitic acid using HCT116 colon cancer cells as an experimental model. We found that KIF2A was localized in the centrosomes. The experimental treatment induced the binding between ROCK1 and KIF2A, although did not increased the protein level of KIF2A. The molecular docking modeling analysis also showed that the two proteins had the binding/interaction potential. We used siRNA of each protein to knockdown their expression level, as a tool to disrupt the ROCK1-KIF2A complex, which attenuated the treatment-induced centrosome amplification. In conclusion, our results suggest that the binding between ROCK1 and KIF2A signals for the diabetes-associated centrosome amplification.

Reciprocal interaction between SIRT6 and APC/C regulates genomic stability

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.

Patterns of selection against centrosome amplification in human cell lines

The presence of extra centrioles, termed centrosome amplification, is a hallmark of cancer. The distribution of centriole numbers within a cancer cell population appears to be at an equilibrium maintained by centriole overproduction and selection, reminiscent of mutation-selection balance. It is unknown to date if the interaction between centriole overproduction and selection can quantitatively explain the intra- and inter-population heterogeneity in centriole numbers. Here, we define mutation-selection-like models and employ a model selection approach to infer patterns of centriole overproduction and selection in a diverse panel of human cell lines. Surprisingly, we infer strong and uniform selection against any number of extra centrioles in most cell lines. Finally we assess the accuracy and precision of our inference method and find that it increases non-linearly as a function of the number of sampled cells. We discuss the biological implications of our results and how our methodology can inform future experiments.