Experimental evolution illustrates gene bypass process for mitosis

Researchers from Nagoya University demonstrated gene bypass events for mitosis using evolutionary repair experiments. They found a novel connection between genes involved in mitosis and glucose metabolism, as published in Proceeding of the National Academy of Sciences of the United States of America. This connection might be a key for an effective treatment of cancer.

Mitosis is a cell division process in which genomic DNA replicates and separates into two new cells. Although it is essential in all eukaryotes, different species use different genes for mitosis. This suggests that during evolution, the essential genes for mitosis have been replaced by other genes and mechanisms. This phenomenon is called bypass of essentiality, but it is unclear how this occurred in mitosis.

Using a technique called experimental evolution, Professor Gohta Goshima and PhD student, Juyoung Kim, of the Graduate School of Science at Nagoya University, replicated gene bypass events for mitosis using yeast cells.

The researchers first screened several mitotic genes to see which genes are “bypassable”. They found that yeast cells lacking a gene called Plo1 could still achieve mitosis and grow. This was unexpected because Plo1 was believed to be essential for various processes during mitosis in both yeast and animal cells. For example, Plo1 is responsible for spindle formation, a necessary step in mitosis.

Without Plo1, how can cells achieve mitosis? Yeast seems to bypass Plo1 and undergo mitosis in multiple ways. One bypass mechanism that caught the researchers’ attention, occurs in the glucose metabolism pathway. The researchers found that yeast cells lacking Plo1 grew in a low glucose environment, as they have several secondary mutations in genes associated with glucose metabolism. In this type of yeast cell, casein kinase I (CK1) became responsible for spindle formation in the absence of Plo1.

This was surprising because glucose metabolism is not directly related to mitosis. However, it reflects previous reports that compensatory mechanisms often emerge from seemingly unrelated gene networks. These conclusions are also consistent with previous understanding that simple environmental changes, such as lack of nutrition, enable the bypass of essentiality during evolution.

In humans, Plk1 is analogous to Plo1. Conducting further investigations using human colon cancer cells, the team found a similar relationship between Plk1 and CK1. CK1 helps in mitosis when Plk1 is impaired, allowing cancer cells to multiply.

As multiple types of human cancer cells show a high level of Plk1, some people have previously proposed using Plk1 inhibitors as antitumor drugs. According to the current finding, however, suppressing both Plk1 and CK1 could be more effective in cancer treatment. This is because cancer cells may develop resistance using CK1 to achieve mitosis. A deeper understanding of the bypass of essentiality is helpful in drug development targeting mitosis.

This work was supported by the Nagoya University Research Fund associated with Japan Science and Technology Agency (JST) SPRING (J.K.), Japan Society for the Promotion of Science (JSPS) KAKENHI Grants 17H01431 (to G.G.) and 19K22383 (to G.G.), JSPS Joint Research Projects with UK Research and Innovation (G.G.), and Uehara Memorial Foundation Grant 202120392 (to G.G.).