Insights into a DNA Repair Pathway Implicated in Breast, Ovarian, and Prostate Cancers

Throughout the course of our lives, DNA can break in response to natural and environmental factors. Thankfully, our bodies have dedicated enzymes and pathways which can glue our broken DNA back together through several different mechanisms, known as DNA repair pathways.

researchers have pieced together 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 cancer, ovarian cancer, and prostate cancer, specifically those involving BRCA1 and BRCA2 mutations — has been laid out step by step in a published article, and the new knowledge could lead to new therapies for cancer.

Out of all DNA repair pathways, TMEJ has been the most elusive.

Richard Wood, PhD, played a key role in the first characterization of polymerase theta in 2003.

Over the next 15 years, multiple labs, including the Wood, Ramsden, and Gupta labs were able to link polymerase theta to DNA repair (TMEJ) and cancer.

Sylvie Doublié, PhD,  then solved the first structure of polymerase theta.

Together, and with other scientists these researchers were dedicated to understanding precisely what steps are involved in TMEJ, and which of those steps polymerase theta does and does not perform.

With the help of these collaborators, Stroik was able to use a wide variety of cutting-edge experimental approaches to fill in the gaps in our understanding of the TMEJ pathway.

Critically, she discovered that another polymerase, called polymerase delta, uses a buddy system with polymerase theta to assist it in this repair pathway.

“It makes a lot of errors and it’s not capable of creating large swaths of DNA at once,” said Stroik.

Stroik had another breakthrough finding: polymerase theta and delta are physically attached to one another.

This new information could prove to be especially useful to drug developers hoping to create a new cancer treatment by drugging this interaction.

Since many cancers make use of the TMEJ pathway to keep tumors alive, many researchers have investigated creating drugs that can interfere with the pathway, essentially preventing cancer from repairing itself, leading to its eventual demise.


Susanna Stroik, Juan Carvajal-Garcia, Dipika Gupta, Alyssa Edwards, Adam Luthman, David W. Wyatt, Rachel L. Dannenberg, Wanjuan Feng, Thomas A. Kunkel, Gaorav P. Gupta, Mark Hedglin, Richard Wood, Sylvie Doublié, Eli Rothenberg, Dale A. Ramsden. Stepwise requirements for polymerases δ and θ in theta-mediated end joining. Nature, 2023; DOI: 10.1038/s41586-023-06729-7

University of North Carolina Health Care. “Scientists piece together DNA repair pathway implicated in breast, ovarian, and prostate cancers.” ScienceDaily. ScienceDaily, 15 November 2023. <>.

Materials provided by University of North Carolina Health Care. Note: Content may be edited for style and length.

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