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.
According to Susanna Stroik, PhD, and Dale Ramsden, PhD, the rockstars in the Department of Biochemistry and Biophysics, this pathway has been found to be upregulated in many patients with hereditary breast cancer, ovarian cancer, and prostate cancer. Specifically, those cancers involving BRCA1 and BRCA2 mutations. In other words, it’s the go-to repair pathway for the cancers that love to party hard.
“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 Stroik with a mischievous twinkle in her eye. “But now that we know more about this pathway, scientists could potentially design a drug to disrupt key pieces of the pathway in cancer cells. It’s like being the DJ at the cancer dance party, selecting the songs to bring down the house. And by house, I mean the cancer.”
Polymerase Theta’s Discovery
Out of all the DNA repair pathways, TMEJ has been the most elusive. It’s like trying to find Waldo at a rave. But finally, in 2003, Richard Wood, PhD, a distinguished professor at University of Texas MD Anderson Cancer Center, played a key role in the first characterization of polymerase theta. Thank you, Dr. Wood, for showing us the way.
Then, over the next 15 years, multiple labs, including the Wood, Ramsden, and Gupta labs (also at Lineberger Comprehensive Cancer Center), linked polymerase theta to DNA repair and cancer. It was like watching a crime solve itself slowly but oh-so-satisfyingly over time. And finally, Sylvie Doublié, PhD, an alumnus of UNC-Chapel Hill, stepped in to solve the first structure of polymerase theta. It was like she found the hidden treasure that had eluded us for so long.
Together with other scientists from Penn State and New York University, these researchers were like detectives on a mission to understand exactly what steps are involved in TMEJ, and which of those steps polymerase theta does and does not perform. It’s like they were playing that childhood game of “follow the leader” with DNA repair pathways.
With the help of these collaborators, Stroik unleashed her inner Sherlock Holmes and used a wide variety of cutting-edge experimental approaches to fill in the gaps in our understanding of the TMEJ pathway. Critically, she discovered that polymerase delta, another one of the DNA repair pathway buddies, uses a buddy system with polymerase theta to assist it in this repair pathway. It’s like they’re a power couple, supporting and complementing each other.
A Unique Buddy System
Stroik’s research showed that polymerase theta, much like your unreliable friend, has its strengths and weaknesses. “It makes a lot of errors and it’s not capable of creating large swaths of DNA at once,” said Stroik, shaking her head in fake exasperation. “But here’s the plot twist: 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, being the impulsive one, acts quickly, grabbing the two single strands of DNA, matching up the perfect base pairs to the break, and holding them together. It’s like a romantic comedy of DNA repair.
However, this often leaves some residual flaps of single stranded DNA at the ends. That’s where polymerase delta, the tidy one, jumps in to cut the extraneous flaps, giving polymerase theta enough room to start synthesizing new DNA to fill in the gaps in the DNA strands. Finally, polymerase delta jumps in one last time to help polymerase theta complete synthesis. It’s like a well-choreographed dance routine, with each partner knowing their moves perfectly.
But here’s the juicy tidbit: Stroik had another breakthrough finding. Polymerases theta and delta are physically attached to one another. It’s like they found their other half in the DNA repair universe. This new information could prove to be especially useful to drug developers hoping to create a new cancer treatment by drugging this interaction. It’s like breaking up the ultimate DNA repair power couple.
Cancer Treatment Potential
Since many cancers make use of the TMEJ pathway to keep tumors alive, many researchers have been scrambling to find ways to interfere with the pathway. They’re like those party poopers who want to shut down the cancer dance party and send everyone home. And Stroik and Ramsden’s new research is like the ultimate party crasher, contributing to ongoing basic studies in polymerases theta and delta, while also aiding new cancer drugs called polymerase theta inhibitors, which are currently in clinical trials. It’s like turning the tables on cancer and showing it who’s boss.
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.
According to Susanna Stroik, PhD, and Dale Ramsden, PhD, the rockstars in the Department of Biochemistry and Biophysics, this pathway has been found to be upregulated in many patients with hereditary breast cancer, ovarian cancer, and prostate cancer. Specifically, those cancers involving BRCA1 and BRCA2 mutations. In other words, it’s the go-to repair pathway for the cancers that love to party hard.
“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 Stroik with a mischievous twinkle in her eye. “But now that we know more about this pathway, scientists could potentially design a drug to disrupt key pieces of the pathway in cancer cells. It’s like being the DJ at the cancer dance party, selecting the songs to bring down the house. And by house, I mean the cancer.”
Polymerase Theta’s Discovery
Out of all the DNA repair pathways, TMEJ has been the most elusive. It’s like trying to find Waldo at a rave. But finally, in 2003, Richard Wood, PhD, a distinguished professor at University of Texas MD Anderson Cancer Center, played a key role in the first characterization of polymerase theta. Thank you, Dr. Wood, for showing us the way.
Then, over the next 15 years, multiple labs, including the Wood, Ramsden, and Gupta labs (also at Lineberger Comprehensive Cancer Center), linked polymerase theta to DNA repair and cancer. It was like watching a crime solve itself slowly but oh-so-satisfyingly over time. And finally, Sylvie Doublié, PhD, an alumnus of UNC-Chapel Hill, stepped in to solve the first structure of polymerase theta. It was like she found the hidden treasure that had eluded us for so long.
Together with other scientists from Penn State and New York University, these researchers were like detectives on a mission to understand exactly what steps are involved in TMEJ, and which of those steps polymerase theta does and does not perform. It’s like they were playing that childhood game of “follow the leader” with DNA repair pathways.
With the help of these collaborators, Stroik unleashed her inner Sherlock Holmes and used a wide variety of cutting-edge experimental approaches to fill in the gaps in our understanding of the TMEJ pathway. Critically, she discovered that polymerase delta, another one of the DNA repair pathway buddies, uses a buddy system with polymerase theta to assist it in this repair pathway. It’s like they’re a power couple, supporting and complementing each other.
A Unique Buddy System
Stroik’s research showed that polymerase theta, much like your unreliable friend, has its strengths and weaknesses. “It makes a lot of errors and it’s not capable of creating large swaths of DNA at once,” said Stroik, shaking her head in fake exasperation. “But here’s the plot twist: 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, being the impulsive one, acts quickly, grabbing the two single strands of DNA, matching up the perfect base pairs to the break, and holding them together. It’s like a romantic comedy of DNA repair.
However, this often leaves some residual flaps of single stranded DNA at the ends. That’s where polymerase delta, the tidy one, jumps in to cut the extraneous flaps, giving polymerase theta enough room to start synthesizing new DNA to fill in the gaps in the DNA strands. Finally, polymerase delta jumps in one last time to help polymerase theta complete synthesis. It’s like a well-choreographed dance routine, with each partner knowing their moves perfectly.
But here’s the juicy tidbit: Stroik had another breakthrough finding. Polymerases theta and delta are physically attached to one another. It’s like they found their other half in the DNA repair universe. This new information could prove to be especially useful to drug developers hoping to create a new cancer treatment by drugging this interaction. It’s like breaking up the ultimate DNA repair power couple.
Cancer Treatment Potential
Since many cancers make use of the TMEJ pathway to keep tumors alive, many researchers have been scrambling to find ways to interfere with the pathway. They’re like those party poopers who want to shut down the cancer dance party and send everyone home. And Stroik and Ramsden’s new research is like the ultimate party crasher, contributing to ongoing basic studies in polymerases theta and delta, while also aiding new cancer drugs called polymerase theta inhibitors, which are currently in clinical trials. It’s like turning the tables on cancer and showing it who’s boss.
