A mutated eye provides a glimpse of a key protein in cancer prevention

The embryo of a wild-type zebrafish above the embryo of a banp mutant zebrafish, both four days after fertilization (dpf). The mutant embryo has smaller eyes (shown with the red arrow) compared to the wild-type. The black arrow shows the cloudy tectum (the top part of the midbrain) in the mutant embryo, representing cell death. Scale bar = 100 μm. The image appeared in the research paper published in eLife. Photo credit: Okinawa Institute of Science and Technology

About 15 years ago, a group of researchers discovered mutant zebrafish. The eyes of these zebrafish did not develop properly, resulting in significantly smaller eyes than wild zebrafish. Well, one of those researchers – Prof. Ichiro Masai, who along with his previous Ph.D. heads the Department of Developmental Neurobiology at the Okinawa Institute of Science and Technology (OIST). student dr Swathy Babu, used this mutation to understand a protein’s role in preventing cell death. This could have far-reaching implications for the development of cancer therapies and for understanding how the cell cycle is regulated.

“Many cells that develop tumors have been reported to have a problem with this protein,” said Prof. Masai, senior author of the study, which was published in eLife. “In addition, the importance of the protein in regulating the cell cycle and aiding in DNA repair has been previously suspected but not rigorously tested.”

Suppose a cell’s DNA is damaged. When the process of replicating the DNA to duplicate the cell takes place, the replication stops at the damaged site. The cell then activates a range of proteins to try to repair the DNA in various ways. But if all pathways the cell uses fail, the cell will die. Prof. Masai hypothesized that they observed an increase in the number of cell deaths in the zebrafish mutants, which led to the eyes not developing properly.

There’s Banp, a protein that researchers have thought for some time to be involved in tumor suppression and cell cycle regulation. However, all previous research has been done on cell cultures, as deleting the gene in mice or other model organisms resulted in embryo death. But zebrafish embryos, which develop outside of the parents’ bodies, provided an ideal model to test the theory.

For her Ph.D. In the Department of Developmental Neurobiology, Dr. Babu the role that Banp played in cell cycle regulation. The gene that encodes the Banp protein is located on chromosome 25. First, the researchers sequenced the mutant fish’s Banp gene and found an extensive mutation in the gene introduced another mutation in the Banp gene. The resulting zebrafish also had eyes that did not develop properly. This complemented their theory that Banp plays a key role in repairing DNA.

The next question dealt with what Banp did and how the mutations affected the development of an organism. When it was recently reported that Banp is an important protein for converting DNA to RNA, the researchers decided to compare the genes expressed in mutant zebrafish with those of wild-type zebrafish. They found that Banp appeared to promote the expression of 31 genes, which had several direct and indirect effects. Specifically, in this study, researchers examined different mechanisms that the cell would use to repair DNA during cell proliferation. They found that each of these mechanisms required proteins produced by the banp gene, which were not produced to the same extent in the mutated version. Without the normal operation of banp, DNA repair simply could not take place.

“Banp appears to be a multiple regulator affecting many different proteins, from DNA repair to cell duplication to tumor suppression,” said Dr. Babu, first author of the research paper.

Thus, mutation on the banp gene appears to be associated with cell death. Scientists hope this research will lead to further investigation of the links to cancer and cell cycle regulation.