IRIC - Institute for Research in Immunology and Cancer

Published on February 25, 2020

Among the arsenal of drugs used in chemotherapy, those that damage DNA or disrupt the formation of microtubules, a major cellular protein filament, prove to be among the most effective, especially if they are used in combination. Why? This is a question that has remained unclear until now…But IRIC researchers and collaborators believe they have identified part of the answer.

The team of Benjamin Kwok, Principal Investigator of the Chemical Biology of Cell Division Unit at IRIC and researchers from the University of Nebraska Medical Center, jointly published an article in the scientific journal eLife on the subject. The group investigated the case of a protein: Kif2C.

Kif2C belongs to the group of kinesins, a family of proteins that normally act like small semi-trailer trucks in cells, moving along the cellular highways that are the microtubules, to transport cargoes from the periphery of the nucleus to ends of the cell or to allow chromosomes separation during cell division. The case of Kif2C differs however. When this protein attaches to microtubules, it causes them to disassemble. This was believed to be its only function until it was discovered that it also associates with…DNA.

Double life

Benjamin Kwok and his collaborators made this discovery while looking for proteins capable of attaching themselves to damaged DNA fragments and contribute to DNA  repair. To do this, they used a bait that simulates damaged DNA strands, and let it bathe in a solution of cellular content. With this approach, the researchers caught a series of proteins already known for their role in repairing DNA, but also Kif2C.

To understand if its presence revealed a new role for this protein, the researchers carried out a series of experiments, starting with a first in which they damaged DNA directly in cells with a laser. They then observed the behavior of Kif2C. In less than a minute, the protein concentrated where the laser had caused some damage, suggesting that its association with damaged DNA was no coincidence.

The IRIC team and their collaborators then wanted to know if this displacement depended on two other proteins involved in cell repair, namely PARP and ATM kinase. By blocking their activity, they concluded that the recruitment of Kif2C to the damaged site depended on these two proteins.

THE question now remained to be answered. Is Kif2C necessary for a repair to take place? To find out, the authors of the article blocked the production of Kif2C in cells which they compared to normal cells by measuring the incorporation of a DNA “repair marker” in these cells.  Their results are clear: in the absence of Kif2C, DNA repairs less frequently, which supports the thesis that its presence is important in the repair process. An importance supported by the lower survival rate of cells where Kif2C was absent.

A link between two worlds

The two known functions of Kif2C now remained to be disentangled. The fact is that the microtubules to which the protein attaches are found in the cytosol of human cells, and not in their nucleus, whereas damaged DNA is, on the contrary, only found in the nucleus. Could the function of Kif2C in microtubules regulation play a role in DNA repair? By blocking this function, the researchers observed to their amazement that this was indeed the case.

This discovery now opens the door to a series of new questions about the possible involvement of microtubules in DNA repair. It also allows us to understand a little better how the drugs used in chemotherapy impact cancer cells, in addition to revealing a new therapeutic target that could be exploited to improve treatments.