3-D snapshot of protein highlights potential drug target for breast cancer

The genome of a cell is under constant attack, suffering DNA damage that requires an army of repair mechanisms to keep the cell healthy and alive. Understanding the behavior of the enzymes defending these assaults helps determine how - and where - cancer gets its foothold and flourishes. New research published in an Advance Online Publication of Nature Structural & Molecular Biology shows that one of these enzymes - human DNA polymerase theta (POLQ) - may be a promising drug therapy target for inhibiting breast cancer.

"The human genome encodes more than 15 different polymerases, which are the essential enzymes that copy our genetic material," says Karl Zahn, Ph.D., University of Vermont postdoctoral associate and first author on the study. "POLQ is known to serve a specialized role - it can perform some tasks that other polymerases are unable to do, including the repair of certain toxic double-strand breaks in the DNA, which can induce genomic instability if left unrepaired."

This genomic instability can sometimes lead to cancer, especially the types of cancer that are most difficult to treat.

Using X-ray crystallography, Zahn and University of Vermont structural biologist Sylvie Doublié, Ph.D., and colleagues determined the first crystal structures of POLQ - recently highlighted as the only DNA polymerase overexpressed in certain breast and ovarian cancers - providing a visual of the DNA repair process.

"The field focused on this enzyme is evolving," says Doublié, senior author on the paper, which is one of several POLQ-related studies published in the last month. The team's work provides a first step in determining how to feasibly pursue POLQ as a cancer drug target.

"Having this new structure really helps inform this process," says Doublié.

Cells in the body normally divide (reproduce) only when new cells are needed. Sometimes, cells in a part of the body grow and divide out of control, which creates a mass of tissue called a tumor. If the cells that are growing out of control are normal cells, the tumor is called benign (not cancerous). If however, the cells that are growing out of control are abnormal and don't function like the body's normal cells, the tumor is called malignant (cancerous).

Cancers are typically named after the part of the body from which they originate. Breast cancer originates in the breast tissue. Like other cancers, breast cancer can invade and grow into the tissue surrounding the breast. It can also travel to other parts of the body and form new tumors, a process called metastasis.

What Causes Breast Cancer?

We do not know what causes breast cancer, although we do know that certain risk factors may put you at higher risk of developing it. A person's age, genetic factors, personal health history, and diet all contribute to breast cancer risk.