A recent study published in the journal Nucleic Acids Research by Rice and St. Jude’s researchers exposes for the first time the structural basis of Pol theta-mediated MMEJ, demonstrating how its unique insertion loops assist sustain short DNA binding while preparing a location for MMEJ repair.
Rice University and St. Jude Children’s Research Hospital in Memphis, Tennessee, have examined one of the mechanisms by which cells repair damaged strands of DNA.
They uncovered information that might enable a certain enzyme become a potential target for precision cancer treatment.
The role of DNA polymerase theta (aka Pol theta) is similar to patching a tyre in that it bridges the dangling single-stranded ends and catalyses DNA synthesis across the break, a process known as microhomology-mediated end joining (MMEJ). MMEJ is a complement to two additional processes that repair DNA double-strand breaks – homologous recombination and non-homologous end joining – but with lesser fidelity since Pol theta is prone to mutation, insertion, and deletion mistakes. The benefit is that MMEJ requires Pol theta to mend a double strand.
A recent study published in the journal Nucleic Acids Research by Rice and St. Jude’s researchers exposes for the first time the structural basis of Pol theta-mediated MMEJ, demonstrating how its unique insertion loops assist sustain short DNA binding while preparing a location for MMEJ repair. The work was conducted by Yang Gao, an associate professor of biosciences at Rice, Ji Sun, an assistant member of the Structural Biology Department at St. Jude, and postdoctoral researchers Chuxuan Li of Rice and Hanwen Zhu of St. Jude.
“When DNA breaks, it’s incredibly damaging for the cell, which has to mend it straight soon,” Gao, a Cancer researcher, explained.
Cancer researcher at the Prevention and Research Institute of Texas (CPRIT) who examines the processes of DNA replication. “One break can kill the cell, and cells, especially cancer cells, do not want to die.
“One of the most common scenarios is when patients have a BRCA1 or BRCA 2 mutation,” he said, explaining that while the genes are healthy, they express DNA-repair proteins, but mutations can cause breast cancer “When a patient has a problem with these genes, the homologous recombination pathway cannot repair them. They must use alternative routes.
“Eight years ago, people discovered that knocking down Pol theta in normal cells does not cause an issue,” Gao explained. “These shortfalls can be deadly if this protein is knocked down in cells with mutant BRCA1 or BRCA2. That is why this has the potential to be a pharmaceutical target.
Normal cells would be unaffected by a Pol theta inhibitor, but cancer cells would be.”
He stated that clinical trials for similar medicines are now ongoing based on other laboratories’ research, but the Rice lab’s discovery provides specifics about the mechanism.
Researchers investigate a DNA repair method for cancer treatment.
