Structure solved at Scripps shows how one human protein reduces potency of chemotherapy

ating agents are chemicals that transfer one of a number of different carbon-chain "alkyl" groups onto the bases of DNA, which change the structure of those bases and often disrupt the transcription or replication of that DNA. This can retard a cell's growth and lead to its deaththe desirable outcome for cancer cells. The damage these agents cause may not be confined to cancer cells, but the toxicity to the cancer cells is usually greater than the toxicity to the rest of the body.

However, the human repair protein O6-alkylguanine-DNA alkyltransferase (AGT), which is one of the body's natural defenses against DNA damage, can inadvertently protect cancer cells from these agents.

AGT is remarkably efficient and repairs DNA extremely rapidly, says Anthony Pegg of the Pennsylvania State University College of Medicine, who has been studying AGT protein for several years and is one of the authors on the study.

However, says Daniels, this protection can cut both ways. "Tumor cell lines hijack [AGT's] function and overexpress the protein to escape therapies," he says. Cells in some tissues, such as the brain, naturally have high levels of AGT. This enables cancers that arise in the brain to resist chemotherapy. Cancer cells in other parts of the body can also use AGT to escape chemotherapy by "upregulating" or expressing excess amounts of AGT. When these cancers do this, they are rendered resistant to alkylating agents.

Wanting to understand how AGT repair works on the molecular level, Daniels and Tainer teamed up with Pegg a few years ago to solve the structure of AGT.

Twist and Grab

Now Daniels and Tainer have solved the structure of AGT bound to DNA. The structure gives a view of how the protein binds to damaged DNA, says Pegg, and this information is useful for designing inhibitors to interfere with AGT's actions. In fact, Pegg has already made such inhibitors of AGT, and some of these are currently being t

Contact: Jason Bardi
Scripps Research Institute

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