Knocking out DNA repair system could boost chemo’s kick

Cells have a way of sensing the damage that certain chemotherapy drugs induce, researchers report. The findings could have important implications for treating cancer.

The busy world inside a cell is directed by its DNA blueprint. When the blueprints change, cells can sicken, die, or become cancerous. To keep DNA in working order, cells have ways to detect and mend damaged DNA.

“Blocking this pathway could be a way to make resistant tumors sensitive again.”

Some of the oldest chemotherapy drugs are known as alkylating agents because they kill cancer cells by adding groups of carbon and hydrogen atoms to—or alkylating—DNA. The extent of the alkylation damage overwhelms the cells’ ability to heal themselves via their DNA repair pathways. And some tumors are abnormally dependent on proteins involved in DNA repair, such that knocking out those proteins kills the tumor cells.

“We found that human cells can sense alkylation damage and mobilize a repair complex specifically suited to repair this kind of injury,” says senior author Nima Mosammaparast, an assistant professor of pathology and immunology, and co-leader of the DNA Metabolism and Repair Working Group at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

“Knocking out this complex may be a way to increase the potency of certain chemotherapy drugs, or to specifically target tumor cells that have become dependent on the repair complex,” she says.

Chemo and DNA repair

Alkylation can happen naturally, which is why cells have this repair system in the first place. Also, certain chemotherapy drugs force it to happen.

Busulfan, used to treat leukemia, and temozolomide, prescribed for brain tumors, alkylate many spots along DNA. It is difficult for the genetic blueprint to be copied accurately where DNA has been alkylated, so such alkylation damage kills the cells.

Studying cells treated with alkylating chemotherapy drugs or with drugs that lead to other kinds of DNA damage, the researchers determined how cells try to mend DNA damage caused specifically by alkylating agents.

They identified a group of proteins that clustered near the spots on the DNA that had been alkylated. Cells that lacked a key member of this protein complex were more likely to die if researchers treated them with alkylating drugs than cells that had the protein, indicating the importance of the protein complex in repairing…

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