Mutated Zebrafish Eye Sheds Light on Elusive DNA Repair Protein

A mutated zebrafish eye has yielded new insights into banp, a protein that has been hypothesized to play a role in regulating the cell cycle, initiating DNA repair, and suppressing tumors. The findings could have vast implications for the development of cancer therapy and for understanding how the cell cycle is regulated.

To date, it has been difficult to study banp, since all previous research on cell cultures involved deleting the gene in mice or other model organisms caused embryo death. But a team from Japan has had success with zebrafish embryos, which develop outside the body of the parent and turned out to be an ideal model for testing the theory. They found that without banp operating normally, DNA repair could not take place. 

“Many cells that develop tumors reportedly have an issue with this protein,” says Professor Ichiro Masai, who leads the Developmental Neurobiology Unit at the Okinawa Institute of Science and Technology (OIST).  “Furthermore, the importance of the protein for regulating the cell cycle and helping DNA repair has also previously been hypothesized, but not rigorously tested.”

When the DNA of a cell is damaged, replication will halt at the damaged point. The cell will then activate a number of proteins to try to repair the DNA in various ways. But if all the pathways that the cell utilizes fail, the cell will die. Masai hypothesized that an increase in the number of cell deaths in the zebrafish mutants was the reason their eyes were significantly smaller than wild zebrafish.

Masai and Dr. Swathy Babu, formerly a PhD student in Masai’s, used the mutant zebrafish to study the role banp plays in regulating the cell cycle. First, they sequenced the banp gene from the mutated fish and found an extensive mutation on the gene. They then took developing zebrafish that did not carry this mutation and introduced another mutation onto the banp gene. The resulting zebrafish also had eyes that did not develop correctly. This added to their theory that banp plays a key role in repairing DNA.

They next looked at what banp did and how the mutations impacted the development of an organism. Following recent reports that banp is an important protein for converting DNA to RNA, the authors decided to compare the expressed genes in mutant zebrafish with those of the wild-type zebrafish. They found that banp seemed to promote the expression of 31 genes, which had multiple direct and indirect impacts. Specifically, they looked at different mechanisms that the cell would use to repair the DNA during cell proliferation. They found that each of these mechanisms required proteins produced by the banp gene that wasn’t produced to the same extent in the mutated version. Without banp operating as usual, DNA repair simply couldn’t take place.

“Banp seems to be a multiple regulator, influencing many different proteins, from DNA repair to cell duplication to tumor suppression,” adds Dr. Babu.

The findings were published recently in the journal eLife. The team hopes the work will lead to further investigations of the links between banp and cancer and cell cycle regulations.