New protein complex gets chromosomes sorted
It is no secret that DNA, in the form of chromosomes, is the building block of life. Incorrect distribution of chromosomes during cell division can have disastrous consequences. Unbalanced chromosome copy, or aneuploidy, is a hallmark of tumors and affects development and survival in all organisms, including humans.
How cells disseminate genetic material has fascinated researchers for centuries. In a study published in June 2020 in Nucleic Acids Research, researchers from the University of Tsukuba, led by Associate Professor Keiji Kimura, have identified a new protein complex, NWC, involved in chromosome distribution.
NWC is associated with the nucleolus, a membrane-less intranuclear structure, and re-locates to the periphery of chromosomes during cell division. This protein complex contains three different proteins: NOL11, WDR43, and Cirhin. NOL11 is usually associated with the nucleolus, and WDR43 and Cirhin are WD-repeat proteins. "This research is important because, to date, the mitotic functions of nucleolar proteins have largely been uncharacterized," says Associate Professor Kimura.
The team examined NOL11 localization in human cells using immunofluorescence. Using a specialized microscope, protein location can be visualized by virtue of its "glow." They found that NOL11 localized to the periphery of chromosomes during mitosis, or nuclear division. Explains Associate Professor Kimura: "When we examined the NOL11 protein we realized that it lacked any functional motifs. We then explored the idea that perhaps it functions in a complex with other proteins."
Using advanced molecular techniques, the research team identified and characterized the NWC complex. They examined the effect of removing individual proteins from the complex and found that all three components are required for NWC to localize to chromosomes and function in mitosis. Reducing the amount of NWC in cells led to incomplete cell cycle progression, with chromosomes failing to separate, misaligned chromosomes, and defects in the location and concentrations of proteins required for accurate chromosome distribution, including Aurora B, the cohesin complex, and histone H3 phosphorylation.
The results presented by Associate Professor Kimura and colleagues show that NWC specifically functions in mitotic chromosome stability through allowing Aurora B to accumulate at the centromeres, partially through regulating histone phosphorylation. Precisely how NWC controls histone phosphorylation near centromeres remains to be determined.
Given that correct chromosome dissemination is essential for the continuation of life and disease prevention, these results may present a new focus in the search for genes that when mutated lead to aneuploidy, or unbalanced chromosome copies.