Protein Found that Aids DNA Repair in Cancer Cells

Protein Found that Aids DNA Repair in Cancer Cells
Credit: CIPhotos/Getty Images

While chemotherapy can be an effective tool to fight cancer by targeting and damaging the DNA of cancers cells to stop them from replicating their genome, some cancer cells may avoid or repair this damage, making them less susceptible to these treatments. Fortunately, researchers at the Faculty of Health and Medical Sciences, University of Copenhagen, report they have uncovered a protein that plays a role in recruiting DNA repair and signaling factors. Their findings may provide hope in making chemotherapy more efficient.

Their findings are published in the journal Molecular Cell in a paper titled, “The ubiquitin ligase RFWD3 is required for translesion DNA synthesis.”

“We have found strong evidence that the protein RFWD3 is responsible for orchestrating the repair of different DNA lesions induced by chemotherapy. If we can inhibit this protein, we could potentially block cells from tolerating DNA lesions, which could lead to more effective chemotherapy in the future,” explained Julien Duxin, group leader at the Novo Nordisk Foundation Center for Protein Research.

The findings are the culmination of three years of research at the Duxin Group. “Since the 1950s and the pioneer work from Sydney Farber, we have been treating cancer patients with different types of chemotherapeutic agents. These are extremely toxic agents, which have been approved in the clinic because they are effective at killing cancer cells. But the truth is that we still don’t know how cells can repair the damage caused by the treatment. It is a huge knowledge gap, which we are trying to fill in with our fundamental research,” he said.

The researchers used extracts from African frogs, which contain the same repair factors as the ones present in our cells. The group identified the protein RFWD3 and observed that the absence of the protein leads to a profound defect in the recruitment of the components needed to repair and tolerate the damage.

“Here, we show that RFWD3 has an additional and essential function safeguarding the integrity of replicating genomes by promoting DNA synthesis across a spectrum of polymerase-stalling lesions,” the investigators wrote. “We show that RFWD3 stimulates ubiquitylation of proteins when these are located on ssDNA. Consequently, in the absence of RFWD3, ubiquitin signaling at ssDNA gaps is severely compromised, which in turn undermines key events required for timely and productive DNA damage bypass.”

Although the researchers have identified the role that RFWD3 plays, further research is needed to study the process of how lesions caused by chemotherapy are repaired inside our cells. “We are setting up different model systems to study this in detail and identify the key enzymes essential to this process. And by knowing those key enzymes we also get key targets that companies can aim to inhibit,” Duxin concluded.