Researchers at the University of Vermont College of Medicine have discovered a potential new drug therapy target for slowing breast cancer growth. Using X-ray crystallography, Karl Zahn, PhD, structural biologist Sylvie Doublié, PhD, and colleagues were able to demonstrate visually in 3-D how the DNA repair process works.
In people who do not have cancer, new cells are being created, damaged, and destroyed all the time. Cancer occurs when the cells overexpress, underexpress, or become damaged to the point where they are no longer able to be repaired. DNA polymerase theta (POLQ) protects against genomic instability by repairing the pathway for DNA double-strand breaks. This kind of instability can lead to hard-to-treat cancers.1
Researchers are investigating molecules that might act specifically on POLQ without inhibiting other necessary polymerases--enzymes that catalyze the formation of a long-chain molecule by linking smaller molecular units. If these drug-like molecules work as the researchers hope, patients with cancer may not experience severe side effects.
The 3-D picture of the protein demonstrates two potential modes of dimerization, which is the chemical reaction that joins two molecular subunits, resulting in the formation of a single dimer. According to the researchers, one structure depicts insertion of ddATP (2', 3'-dideoxyadenosine-5'-triphosphate) opposite an abasic-site analog during translesion DNA synthesis, and the second structure describes a cognate ddGTP (2', 3'-dideoxyguanosine-5'-triphosphate) complex. Polymerase θ uses a specialized thumb subdomain to establish unique upstream contacts to the primer DNA strand, including an interaction with the 3′-terminal phosphate from one of five distinctive insertion loops. These observations demonstrate how polymerase θ grasps the primer to bypass DNA lesions, or extend poorly annealed DNA termini to mediate end-joining.2
POLQ is overexpressed in ovarian, lung, and oral cancers, and may be found in other cancer types as well. This in turn would positively affect many patients across the cancer spectrum and may be an additional targeted therapy treatment area to focus on.
- Nachbur J. (2015). Doublie and Zahn’s 3-D Snapshot of Protein Highlights Potential Drug Target for Breast Cancer. The University of Vermont College of Medicine.
- Zahn KE, Averill AM, Aller P. et al. (2015). Human DNA polymerase θ grasps the primer terminus to mediate DNA repair. Nature Structural & Molecular Biology.