Our DNA is not indestructible. 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.

Some cancers, however, can hijack these pathways for their own benefit. The 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 in Nature, and the new knowledge could lead to new therapies for cancer.

“People with these breast cancer mutations, their cancers rely on polymerase theta's repair pathway to keep the tumors alive and repair DNA damage in the cancerous tissue,” said an author. “Now that we know more about this pathway, scientists could, in theory, produce a drug that could disrupt key pieces of the pathway in cancer cells, as opposed to using

Over the next 15 years, multiple labs were able to link polymerase theta to DNA repair (TMEJ) and cancer. The 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, and cutting-edge experimental approaches to fill in the gaps in our understanding of the TMEJ pathway. Critically, the authors discovered that another polymerase, called polymerase delta, uses a buddy system with polymerase theta to assist it in this repair pathway.

The research showed that polymerase theta is good at some things, but not others.

“It makes a lot of errors and it's not capable of creating large swaths of DNA at once,” said the author. “What was so beautiful and kind of elegant about the whole discovery is that there are two different enzymes alternating between pathway steps and helping each other out.”

When a double stranded break occurs, both strands of DNA are cut at the same spot, much like scissors severing a braid of hair. Polymerase theta acts quickly, grabbing the two single strands of DNA, matching up the closest base pairs to the break, and holding them together.

However, this often leaves some residual flaps of single stranded DNA at the ends. Polymerase delta jumps in to cut the extraneous flaps, giving polymerase theta enough room to start synthesizing new DNA to fill in gaps in the DNA strands. Finally, polymerase delta jumps in one last time to help polymerase theta complete synthesis.

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.

https://www.nature.com/articles/s41586-023-06729-7