Our DNA is not indestructible. Throughout our lives, DNA can break in response to physical and environmental factors. Fortunately, our bodies have dedicated enzymes and pathways that can patch up our broken DNA through several different mechanisms known as DNA repair pathways.
Some cancers, however, can subvert these pathways to their own advantage. Susanna Stroik, PhD, and Dale Ramsden, PhD, both researchers in the Department of Biochemistry and Biophysics at the UNC School of Medicine and the UNC Lineberger Comprehensive Cancer Center, combined the lesser-known DNA repair pathway, called polymerase theta-mediated end-joining (TMEJ).
The pathway — which has been found to be upregulated in many patients with hereditary breast, ovarian and prostate cancers, especially those with BRCA1 and BRCA2 mutations — has been shown step-by-step in a published article in Natureand the new knowledge could lead to new treatments for cancer.
“People with these breast cancer mutations, their cancers rely on the polymerase theta repair pathway to keep tumors alive and repair DNA damage in the cancer tissue,” said Stroik, a postdoctoral researcher in the Ramsden lab. “Now that we know more about this pathway, scientists could, in theory, produce a drug that could disrupt key parts of the pathway in cancer cells, as opposed to using conventional chemotherapies that destroy healthy cells along with the cancer.” .
The discovery of polymerase Theta
Of all the DNA repair pathways, TMEJ has been the most elusive. Richard Wood, PhD, Distinguished Professor at the University of Texas MD Anderson Cancer Center played a key role in the first characterization of polymerase theta in 2003.
Over the next 15 years, several laboratories, including those of Wood, Ramsden, and Gupta (also at the Lineberger Comprehensive Cancer Center), were able to link polymerase theta to DNA repair (TMEJ) and cancer. Sylvie Doublié, PhD, a graduate of UNC-Chapel Hill and professor of microbiology and molecular genetics at the University of Vermont, then solved the first structure of polymerase theta.
Together, and with other scientists from Penn State and New York University, these researchers devoted themselves to understanding exactly the steps involved in TMEJ and which of these steps polymerase theta does and which does not.
With the help of these collaborators, Stroik was able to use a wide variety of cutting-edge experimental approaches to fill the gaps in our understanding of the TMEJ pathway. Importantly, he discovered that another polymerase, called polymerase delta, uses a buddy system with polymerase theta to help it along this repair pathway.
A unique buddy system
Stroik’s research showed that polymerase theta is good at some things, but not at others.
“It makes a lot of mistakes and is not capable of generating large areas of DNA at once,” Stroik said. “What was so beautiful and elegant about the whole discovery is that there are two different enzymes that switch between the steps of the pathway and help each other.”
When a double-strand break occurs, both strands of DNA are cut at the same point, like scissors cutting a strand of hair. Polymerase theta acts quickly, grabbing the two single strands of DNA, matching the base pairs closest to the break and holding them together.
However, this often leaves some residual strands of single-stranded DNA at the ends. Polymerase delta jumps over to cut the foreign strands, giving polymerase theta enough room to begin synthesizing new DNA to fill gaps in the DNA strands. Finally, polymerase delta jumps in one last time to help complete polymerase theta synthesis.
Stroik had another breakthrough: the theta and delta polymerases are naturally linked to each other. This new information could prove especially useful to drug developers hoping to create a new cancer treatment by medicating this interaction.
Cancer treatment potential
Since many cancers use the TMEJ pathway to keep tumors alive, many researchers have investigated creating drugs that can interfere with the pathway, effectively preventing the cancer from repairing itself, leading to its eventual disappearance.
“Whenever you find new pieces of trail, you can drug it,” Ramsden said.
Stroik and Ramsden’s new research will contribute to ongoing basic studies of theta and delta polymerases, while also helping new cancer drugs called theta polymerase inhibitors, which are currently in clinical trials.