Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia.
Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia.
Int J Mol Sci. 2022 Apr 8;23(8):4139. doi: 10.3390/ijms23084139.
The accurate segregation of sister chromatids is complex, and errors that arise throughout this process can drive chromosomal instability and tumorigenesis. We recently showed that methylglyoxal (MGO), a glycolytic by-product, can cause chromosome missegregation events in lymphocytes. However, the underlying mechanisms of this were not explored. Therefore, in this study, we utilised shotgun proteomics to identify MGO-modified proteins, and label-free quantitation to measure changes in protein abundance following exposure to MGO. We identified numerous mitotic proteins that were modified by MGO, including those involved in the separation and cohesion of sister chromatids. Furthermore, the protein abundance of Securin, an inhibitor of sister chromatid separation, was increased following treatment with MGO. Cytological examination of chromosome spreads showed MGO prevented sister chromatid separation, which was associated with the formation of complex nuclear anomalies. Therefore, results from this study suggest MGO may drive chromosomal instability by preventing sister chromatid separation.
姐妹染色单体的精确分离很复杂，在这个过程中出现的错误会导致染色体不稳定和肿瘤发生。我们最近表明，糖酵解副产物甲基乙二醛 (MGO) 可导致淋巴细胞中的染色体错误分离事件。然而，这背后的机制尚未被探索。因此，在这项研究中，我们利用鸟枪法蛋白质组学来鉴定 MGO 修饰的蛋白质，并进行无标记定量分析，以测量暴露于 MGO 后蛋白质丰度的变化。我们鉴定了许多有丝分裂蛋白被 MGO 修饰，包括参与姐妹染色单体分离和黏合的蛋白。此外，MGO 处理后，姐妹染色单体分离抑制剂 Securin 的蛋白丰度增加。染色体铺片的细胞学检查显示，MGO 阻止了姐妹染色单体的分离，这与复杂核异常的形成有关。因此，这项研究的结果表明，MGO 可能通过阻止姐妹染色单体分离来驱动染色体不稳定。
